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1. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool

Author: Frédéric Tran Mau-Them, Julian Delanne, Anne-Sophie Denommé-Pichon, Hana Safraou, Ange-Line Bruel, Antonio Vitobello, Aurore Garde, Sophie Nambot, Nicolas Bourgon, Caroline Racine, Arthur Sorlin, Sébastien Moutton, Nathalie Marle, Thierry Rousseau, Paul Sagot, Emmanuel Simon, Catherine Vincent-Delorme, Odile Boute, Cindy Colson, Florence Petit, Marine Legendre, Sophie Naudion, Caroline Rooryck, Clément Prouteau, Estelle Colin, Agnès Guichet, Alban Ziegler, Dominique Bonneau, Godelieve Morel, Mélanie Fradin, Alinoé Lavillaureix, Chloé Quelin, Laurent Pasquier, Sylvie Odent, Gabriella Vera, Alice Goldenberg, Anne-Marie Guerrot, Anne-Claire Brehin, Audrey Putoux, Jocelyne Attia, Carine Abel, Patricia Blanchet, Constance F. Wells, Caroline Deiller, Mathilde Nizon, Sandra Mercier, Marie Vincent, Bertrand Isidor, Jeanne Amiel, Rodolphe Dard, Manon Godin, Nicolas Gruchy, Médéric Jeanne, Elise Schaeffer, Pierre-Yves Maillard, Frédérique Payet, Marie-Line Jacquemont, Christine Francannet, Sabine Sigaudy, Marine Bergot, Emilie Tisserant, Marie-Laure Ascencio, Christine Binquet, Yannis Duffourd, Christophe Philippe, Laurence Faivre, and Christel Thauvin-Robinet
Subjects: exome sequencing (ES), chromosomal microarray, prenatal, fetal, diagnostic yield, Genetics, QH426-470
Abstract: Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.
Published: 2023
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2. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author: Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, and Antonio Vitobello
Subjects: genome sequencing, RNA-seq, optical genome mapping, long-read sequencing, clinical diagnoses, Biology (General), QH301-705.5
Abstract: Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
Published: 2023
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3. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Author: Estelle Colin, Yannis Duffourd, Emilie Tisserant, Raissa Relator, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Hana Safraou, Julian Delanne, Nolwenn Jean-Marçais, Boris Keren, Bertrand Isidor, Marie Vincent, Cyril Mignot, Delphine Heron, Alexandra Afenjar, Solveig Heide, Anne Faudet, Perrine Charles, Sylvie Odent, Yvan Herenger, Arthur Sorlin, Sébastien Moutton, Jennifer Kerkhof, Haley McConkey, Martin Chevarin, Charlotte Poë, Victor Couturier, Valentin Bourgeois, Patrick Callier, Anne Boland, Robert Olaso, Christophe Philippe, Bekim Sadikovic, Christel Thauvin-Robinet, Laurence Faivre, Jean-François Deleuze, and Antonio Vitobello
Subjects: undiagnosed neurodevelopmental diseases, genome sequencing, transcriptome sequencing, DNA methylation analysis, translational research, Biology (General), QH301-705.5
Abstract: Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
Published: 2022
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4. The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders

Author: Julian Delanne, Ange-Line Bruel, Frédéric Huet, Sébastien Moutton, Sophie Nambot, Margot Grisval, Nada Houcinat, Paul Kuentz, Arthur Sorlin, Patrick Callier, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Daphné Lehalle, Salima El Chehadeh, Christine Francannet, Marine Lebrun, Laetitia Lambert, Marie-Line Jacquemont, Marion Gerard-Blanluet, Jean-Luc Alessandri, Marjolaine Willems, Julien Thevenon, Mondher Chouchane, Véronique Darmency, Clémence Fatus-Fauconnier, Sébastien Gay, Marie Bournez, Alice Masurel, Vanessa Leguy, Yannis Duffourd, Christophe Philippe, François Feillet, Laurence Faivre, and Christel Thauvin-Robinet
Subjects: Inherited metabolic disorders, Exome sequencing, Intellectual disability, Developmental delay, Genotype first, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable. Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
Published: 2021
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5. Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers

Author: Anne-Laure Renault, Noura Mebirouk, Laetitia Fuhrmann, Guillaume Bataillon, Eve Cavaciuti, Dorothée Le Gal, Elodie Girard, Tatiana Popova, Philippe La Rosa, Juana Beauvallet, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Catherine Dubois d’Enghien, Anthony Laugé, Walid Chemlali, Virginie Raynal, Martine Labbé, Ivan Bièche, Sylvain Baulande, Jacques-Olivier Bay, Pascaline Berthet, Olivier Caron, Bruno Buecher, Laurence Faivre, Marc Fresnay, Marion Gauthier-Villars, Paul Gesta, Nicolas Janin, Sophie Lejeune, Christine Maugard, Sébastien Moutton, Laurence Venat-Bouvet, Hélène Zattara, Jean-Pierre Fricker, Laurence Gladieff, Isabelle Coupier, CoF-AT, GENESIS, kConFab, Georgia Chenevix-Trench, Janet Hall, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Nadine Andrieu, and Fabienne Lesueur
Subjects: ATM, Breast tumour, Pathology, Genetic instability, OncoScan array, Copy number, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. Methods To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. Results We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22–23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially ‘druggable’ genes that would allow patients to be directed towards tailored therapeutic strategies. Conclusions Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.
Published: 2018
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6. Rare variants in PPFIA3 cause delayed development, intellectual disability, autism, and epilepsy

Author: Maimuna S. Paul, Sydney L. Michener, Hongling Pan, Jessica M. Pfliger, Jill A. Rosenfeld, Vanesa C. Lerma, Alyssa Tran, Megan A. Longley, Richard A. Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L. Mester, Maria J. Guillen Sacoto, Richard Person, Pamela P. McDonnell, Stacey R. Cohen, Laina Lusk, Ana S.A. Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé- Pichon, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E. Scheffer, Gemma L. Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A. Bacino, Brendan H. Lee, and Hsiao-Tuan Chao
Subjects: Article
Abstract: PPFIA3encodes the Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3 (PPFIA3), which is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family involved in synaptic vesicle transport and presynaptic active zone assembly. The protein structure and function are well conserved in both invertebrates and vertebrates, but human diseases related to PPFIA3 dysfunction are not yet known. Here, we report 14 individuals with rare mono-allelicPPFIA3variants presenting with features including developmental delay, intellectual disability, hypotonia, autism, and epilepsy. To determine the pathogenicity ofPPFIA3variantsin vivo, we generated transgenic fruit flies expressing either human PPFIA3 wildtype (WT) or variant protein using GAL4-UAS targeted gene expression systems. Ubiquitous expression with Actin-GAL4 showed that thePPFIA3variants had variable penetrance of pupal lethality, eclosion defects, and anatomical leg defects. Neuronal expression with elav-GAL4 showed that thePPFIA3variants had seizure-like behaviors, motor defects, and bouton loss at the 3rdinstar larval neuromuscular junction (NMJ). Altogether, in the fly overexpression assays, we found that thePPFIA3variants in the N-terminal coiled coil domain exhibited stronger phenotypes compared to those in the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of flyLiprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of humanPPFIA3WT, suggesting human PPFIA3 protein function is partially conserved in the fly. However, thePPFIA3variants failed to rescue lethality. Altogether, the human and fruit fly data reveal that the rarePPFIA3variants are dominant negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.
Published: 2023

7. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders

Author: Afshin Saffari, Tracy Lau, Homa Tajsharghi, Ehsan Ghayoor Karimiani, Ariana Kariminejad, Stephanie Efthymiou, Giovanni Zifarelli, Tipu Sultan, Mehran Beiraghi Toosi, Sahar Sedighzadeh, Victoria Mok Siu, Juan Darío Ortigoza-Escobar, Aisha M AlShamsi, Shahnaz Ibrahim, Nouriya Abbas Al-Sannaa, Walla Al-Hertani, Whalen Sandra, Mark Tarnopolsky, Shahryar Alavi, Chumei Li, Debra-Lynn Day-Salvatore, Maria Jesús Martínez-González, Kristin M Levandoski, Emma Bedoukian, Suneeta Madan-Khetarpal, Michaela J Idleburg, Minal Juliet Menezes, Aishwarya Siddharth, Konrad Platzer, Henry Oppermann, Martin Smitka, Felicity Collins, Monkol Lek, Mohmmad Shahrooei, Maryam Ghavideldarestani, Isabella Herman, John Rendu, Julien Faure, Janice Baker, Vikas Bhambhani, Laurel Calderwood, Javad Akhondian, Shima Imannezhad, Hanieh Sadat Mirzadeh, Narges Hashemi, Mohammad Doosti, Mojtaba Safi, Najmeh Ahangari, Paria Najarzadeh Torbati, Soheila Abedini, Vincenzo Salpietro, Elif Yilmaz Gulec, Safieh Eshaghian, Mohammadreza Ghazavi, Michael T Pascher, Marina Vogel, Angela Abicht, Sébastien Moutton, Ange-Line Bruel, Claudine Rieubland, Sabina Gallati, Tim M Strom, Hanns Lochmüller, Mohammad Hasan Mohammadi, Javeria Raza Alvi, Elaine H Zackai, Beth A Keena, Cara M Skraban, Seth I Berger, Erin H Andrew, Elham Rahimian, Michelle M Morrow, Ingrid M Wentzensen, Francisca Millan, Lindsay B Henderson, Hormos Salimi Dafsari, Heinz Jungbluth, Natalia Gomez-Ospina, Anne McRae, Merlene Peter, Danai Veltra, Nikolaos M Marinakis, Christalena Sofocleous, Farah Ashrafzadeh, Davut Pehlivan, Johannes R Lemke, Judith Melki, Audrey Benezit, Peter Bauer, Denisa Weis, James R Lupski, Jan Senderek, John Christodoulou, Wendy K Chung, Rose Goodchild, Amaka C Offiah, Andres Moreno-De-Luca, Mohnish Suri, Darius Ebrahimi-Fakhari, Henry Houlden, and Reza Maroofian
Subjects: NDD, biallelic variation, AMC5, 610 Medicine & health, Neurology (clinical), Torsin-1A, 610 Medizin und Gesundheit, arthrogryposis multiplex congenita 5, Medical Genetics, Medicinsk genetik
Abstract: In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival. CC BY 4.0Correspondence to: Reza MaroofianDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKE-mail: R.Maroofian@ucl.ac.ukA.S. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SA 4171/1-1. H.H. is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). S.E. is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’. This work was supported in part by the US National Institutes of Health R35 NS105078 and MDA#512848 to J.R.L., a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542) and NHGRI Genomics Research to Elucidate Genetics of Rare (BCM-GREGoR U01 HG011758). D.P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s Hospital Foundation. H.T. has been supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no. 608473. H.S.D. is supported by the Cologne Clinician Scientist Program/Faculty of Medicine/University of Cologne and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project No. 413543196). H.J. has been supported by a grant from the European Union (H2020- MSCA-ITN-2017). A.M.D. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (grant 1R01HD104938-01A1). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This research was funded in part by the Wellcome Trust (WT093205MA, WT104033AIA and the Synaptopathies Strategic Award, 165908) as well as the Medical Research Council (MRC) (MR/S01165X/1, MR/ S005021/1, G0601943). Additonally, we are grateful for funding from The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer’s Research UK (ARUK) and CureDRPLA.
Published: 2023
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8. Microdeletions at 19p13.11p12 in five individuals with neurodevelopmental delay

Author: Melissa Rieger, Sébastien Moutton, Sarah Verheyen, Katharina Steindl, Bernt Popp, Bruno Leheup, Céline Bonnet, Beatrice Oneda, Anita Rauch, André Reis, Mandy Krumbiegel, and Ulrike Hüffmeier
Subjects: Phenotype, Neurodevelopmental Disorders, De Lange Syndrome, Genetics, Humans, General Medicine, Chromosome Deletion, Telomere, Chromosomes, Human, Pair 19, Genetics (clinical)
Abstract: Only few copy number variants at chromosome 19p13.11 have been reported, thus associated clinical information is scarce. Proximal to these copy number losses, we now identified deletions in five unrelated individuals with neurodevelopmental disorders. They presented with psychomotor delay as well as behavioral and sleeping disorders, while complex cardiovascular, skeletal, and various other malformations were more variable. Dysmorphic features were rather unspecific and not considered as a recognizable gestalt. Neither of the analyzed parents carried their offsprings' deletions, indicating de novo occurrence. The deletion sizes ranged between 0.7 and 5.2 Mb, were located between 18 and 24 megabases from the telomere, and contained a variable number of protein-coding genes (n = 25-68). Although not all microdeletions shared a common region, the smallest common overlap of some of the deletions provided interesting insights in the chromosomal region 19p13.11p12. Diligent literature review using OMIM and Pubmed did not identify a satisfying candidate gene for neurodevelopmental disorders. In the literature, a de novo in-frame deletion in MAU2 was considered pathogenic in an individual with Cornelia de Lange syndrome. Therefore, the clinical differential diagnosis of this latter syndrome in one individual and the encompassment of MAU2 in three individuals' deletions suggest clinical and genetic overlap with this specific syndrome. Three of the four here reported individuals with deletion encompassing GDF1 had different congenital heart defects, suggesting that this gene's haploinsufficiency might contribute to the cardiovascular phenotype, however, with reduced penetrance. Our findings indicate an association of microdeletions at 19p13.11/ 19p13.11p12 with neurodevelopmental disorders, variable symptoms, and malformations, and delineate the phenotypic spectrum of deletions within this genomic region.
Published: 2023
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9. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network

Author: Robert Olaso, Adeline Prost, Anne-Sophie Denommé-Pichon, Magali Gorce, Anne Boland, Mélanie Fradin, Magalie Barth, Mathilde Nizon, Antonio Vitobello, Dominique Bonneau, Bertrand Isidor, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Victor Couturier, Caroline Racine, Céline Besse, Marie Vincent, Bertrand Fin, Yline Capri, Alban Ziegler, Ange-Line Bruel, Yannis Duffourd, Christophe Philippe, P. Callier, Sébastien Moutton, Aurore Garde, Médéric Jeanne, Annick Toutain, Sophie Nambot, Delphine Bacq-Daian, Charlotte Poë, Emilie Tisserant, Aurélien Juven, Julien Van-Gils, Tiffany Busa, Laurent Pasquier, Sabine Sigaudy, Arthur Sorlin, Thibaud Jouan, Philippine Garret, Corinne Chantegret, Julian Delanne, Cyril Flamant, Alinoë Lavillaureix, Clement Prouteau, Paul Rollier, Laurence Faivre, and Jean-François Deleuze
Subjects: Protocol (science), Hospital network, medicine.medical_specialty, business.industry, Infant, Newborn, Infant, Pilot Projects, Context (language use), Disease, Hospitals, Article, Intensive Care Units, Intensive care, Genetics, medicine, Etiology, Feasibility Studies, Humans, Prospective Studies, Duration (project management), Child, Intensive care medicine, business, Genetics (clinical), Blood sampling
Abstract: Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.
Published: 2021
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10. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Marjolaine Willems, Benjamin Durand, Boris Keren, Kristina Pilekær Sørensen, Rosanna Weksberg, Magalie Barth, Christina Fagerberg, Cyril Mignot, Laurence Perrin, Lucas Bronicki, Nathalie Drouot, Imene Boujelbene, Marc Abramowicz, Maria Kibaek, Bertrand Isidor, Thierry Bienvenu, Mathilde Nizon, Perrine Charles, Laurent Pasquier, Yann Herault, Marie Christine Birling, Bruno Delobel, Michel Guipponi, Lydie Burglen, Mélanie Fradin, Anne Sophie Denommé, Florence Demurger, Benjamin Cogné, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Christèle Dubourg, Alice Goldenberg, Christine Francannet, Jean-Louis Mandel, Laurence Faivre, Jérémie Courraud, Anne Marie Guerrot, Julia Metreau, Loréline Genschik, Bénédicte Demeer, Marie Vincent, Mathilde Renaud, Julien Thevenon, Sandrine Passemard, Christine Coubes, Amélie Piton, David Geneviève, Maria del Mar Muniz Moreno, Bénédicte Gérard, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Salima El Chehadeh, Katrine M Johannesen, Julie D. Thompson, Cathrine Elisabeth Tronhjem, Pascale Saugier, Elise Schaefer, Eric Chater-Diehl, Séverine Drunat, Rikke S. Møller, Paul Kuentz, Claire Feger, Albert David, Antonio Vitobello, Marlène Rio, Khaoula Khachnaoui, Joane Svane, Stéphane Auvin, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Universitaire de Genève, Children's hospital of Eastern Ontario Research Institute [Ottawa, canada] (CHEO), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Hôpital Robert Debré, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], CHU Clermont-Ferrand, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Odense University Hospital (OUH), CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Odense University Hospital [Odense, Denmark], Centre Hospitalier Universitaire [Grenoble] (CHU), Groupe Hospitalier du Havre, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut Clinique de la Souris, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Hôpital Cochin [AP-HP], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), University of Toronto, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune, univOAK, Archive ouverte, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], DYRK1A, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Protein Serine-Threonine Kinases, Biology, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, medicine, Animals, Humans, Missense mutation, Kinase activity, Gene, Genetics (clinical), Cellular localization, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Protein-Tyrosine Kinases, medicine.disease, Phenotype, Human genetics, 3. Good health, 030220 oncology & carcinogenesis, Microcephaly
Abstract: Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene. Graphic abstract: [Figure not available: see fulltext.]
Published: 2021
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11. Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cells differentiation

Author: Marion Coolen, Nami Altin, Karthyayani Rajamani, Eva Pereira, Karine Siquier-Pernet, Emilia Puig Lombardi, Nadjeda Moreno, Giulia Barcia, Marianne Yvert, Annie Laquerrière, Aurore Pouliet, Patrick Nitschké, Nathalie Boddaert, Antonio Rausell, Féréchté Razavi, Alexandra Afenjar, Thierry Billette de Villemeur, Almundher Al-Maawali, Khalid Al-Thihli, Julia Baptista, Ana Beleza-Meireles, Catherine Garel, Marine Legendre, Antoinette Gelot, Lydie Burglen, Sébastien Moutton, Vincent Cantagrel, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), URC, hôpital Necker Enfants Maladies, Paris, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Sultan Qaboos University (SQU), Peninsula Medical School, University Hospitals Bristol, Hôpital des Enfants - Groupe hospitalier Pellegrin - CHU de Bordeaux, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016)
Subjects: Brain Diseases, Developmental Disabilities, Neurogenesis, Histone-Lysine N-Methyltransferase, Nervous System Malformations, Article, Mice, Purkinje Cells, Cerebellum, Mutation, Genetics, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), Zebrafish, ComputingMilieux_MISCELLANEOUS, Brain Stem, Transcription Factors
Abstract: Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.
Published: 2022
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12. Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation

Author: Marta Massimello, Delphine Héron, Tania Attié-Bitach, Myrtille Spentchian, Anne Faudet, Marie-Amélie Rocchisanni, Laurent Mandelbrot, Alexandra Benachi, Julien Saada, Florence Bretelle, Stéphanie Friszer, Paul Maurice, Catherine Garel, Julien Buratti, Mathilde Nizon, Valérie Layet, Jean-Marie Jouannic, Thierry Billette de Villemeur, Corinne Mach, Mathieu Milh, Lucie Guilbaud, Stéphanie Valence, Agnès Guët, Genevieve Quenum‐Miraillet, Sébastien Moutton, Rodolphe Dard, Sandra Chantot-Bastaraud, Valérie Olin, Magali Gorce, Daphné Lehalle, Marta Spodenkiewic, Marie-Laure Moutard, Linda Mouthon, Solveig Heide, Elodie Lejeune, Vassili Tsatsaris, Claire Beneteau, Marie Vincent, Laurent Guibaud, Sandra Whalen, Cyril Mignot, Vincent des Portes, Eléonore Blondiaux, Mathilde Lefebvre, Audrey Putoux, Boris Keren, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de gynécologie-obstétrique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Hospices Civils de Lyon, Departement de Neurologie (HCL), Hospices Civils de Lyon (HCL), Service de Gynécologie et Obstétrique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Reims (CHU Reims), Groupe Hospitalier du Havre, CHI Poissy-Saint-Germain, Hôpital Louis Mourier - AP-HP [Colombes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], AP-HP - Hôpital Antoine Béclère [Clamart], CHU Necker - Enfants Malades [AP-HP], Sorbonne Université (SU), Centre de Référence pour les Maladies Rares à expression psychiatrique (CRMR pour les maladies rares à expresion psychiatrique), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique médicale [CHU Pitié-Salpêtrière], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Nord [CHU - APHM], Hôpital Cochin [AP-HP], Groupe Hospitalier du Havre Hôpital Jacques Monod (MONTIVILLIERS) (GHH), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], CHU Dijon, and Couvet, Sandrine
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, prenatal, [SDV]Life Sciences [q-bio], [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030105 genetics & heredity, MESH: Corpus Callosum, Corpus callosum, Ultrasonography, Prenatal, prenatal exome sequencing, Corpus Callosum, 03 medical and health sciences, Fetus, MESH: Pregnancy, Pregnancy, MESH: Child, Intellectual disability, medicine, Humans, Exome, Prospective Studies, Child, Prospective cohort study, Agenesis of the corpus callosum, Genetics (clinical), Exome sequencing, MESH: Exome, MESH: Humans, business.industry, MESH: Ultrasonography, Prenatal, MESH: Fetus, medicine.disease, MESH: Prospective Studies, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, agenesis of the corpus callosum, Abnormality, business, anomaly of the corpus callosum, exome sequencing, MESH: Female
Abstract: International audience; Purpose: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC).Methods: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered.Results: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy.Conclusion: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.
Published: 2020
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13. <scp>Next‐generation</scp> sequencing approaches and challenges in the diagnosis of developmental anomalies and intellectual disability

Author: Frédéric Tran Mau-Them, Antonio Vitobello, Julian Delanne, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Sophie Nambot, P. Callier, Laurence Faivre, Ange-Line Bruel, Christophe Philippe, Yannis Duffourd, Arthur Sorlin, and Christel Thauvin-Robinet
Subjects: 0301 basic medicine, Computer science, Developmental Disabilities, Computational Biology, High-Throughput Nucleotide Sequencing, Genomics, 030105 genetics & heredity, medicine.disease, Data science, Human genetics, DNA sequencing, 03 medical and health sciences, 030104 developmental biology, Intellectual Disability, Mutation, Intellectual disability, Genetics, medicine, Humans, Identification (biology), Genetic Testing, Genetics (clinical)
Abstract: Recent advances in next-generation sequencing (NGS) technologies have revolutionized the field of human genetics. Alongside a broad panel of bioinformatics tools and databases, NGS technologies have unprecedentedly improved the molecular diagnosis rate and the identification of new genes associated with rare disorders. However, about 50% of patients remain without a final diagnosis. Here, we highlight the utility of NGS applications in developmental anomalies and intellectual disability, illustrating their main advantages and pitfalls. Through specific examples, we suggest novel strategies and tools for identifying the molecular bases in the remaining patients, and we outline future challenges.
Published: 2020
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14. Discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates

Author: Emmanuelle Szenker-Ravi, Tim Ott, Muznah Khatoo, Anne Moreau de Bellaing, Wei Xuan Goh, Yan Ling Chong, Anja Beckers, Darshini Kannesan, Guillaume Louvel, Priyanka Anujan, Vydianathan Ravi, Carine Bonnard, Sébastien Moutton, Patric Schoen, Mélanie Fradin, Estelle Colin, André Megarbane, Linda Daou, Ghassan Chehab, Sylvie Di Filippo, Caroline Rooryck, Jean-François Deleuze, Anne Boland, Nicolas Arribard, Rukiye Eker, Sumanty Tohari, Alvin Yu-Jin Ng, Marlène Rio, Chun Teck Lim, Birgit Eisenhaber, Frank Eisenhaber, Byrappa Venkatesh, Jeanne Amiel, Hugues Roest Crollius, Christopher T. Gordon, Achim Gossler, Sudipto Roy, Tania Attie-Bitach, Martin Blum, Patrice Bouvagnet, Bruno Reversade, ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Genome Institute of Singapore (GIS), University of Hohenheim, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Institute of Molecular and Cell Biology [Singapore, Singapore] (IMCB / A*STAR), National University Hospital [Singapore] (NUH), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hannover Medical School [Hannover] (MHH), REBIRTH Cluster of Excellence [Hannover], Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecologie Systématique et Evolution (ESE), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hammersmith Hospital NHS Imperial College Healthcare, Skin Research Institute of Singapore [Singapore, Singapore] (SRIS / A*STAR), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Praxis Dr Patric SCHÖN [Oberschleissheim, Germany] (2PS), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Gilbert and Rose-Marie Chagoury School of Medicine [Lebanese American University], Lebanese American University (LAU), Institut Jérôme Lejeune, Université Saint-Joseph de Beyrouth (USJ), Lebanese University [Beirut] (LU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Istanbul University, Assistance publique-Hôpitaux de Paris - Espace éthique (AP-HP Espace éthique), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Singapore Institute of Food and Biotechnology Innovation [Singapore, Singapore] (SIFBI / A*STAR ), Bioinformatics Institute [Singapore, Singapore] (BII / A*STAR), Nanyang Technological University [Singapour], National University of Singapore (NUS), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Maison de la Femme de la Mère et de l'Enfant [CHU de la Martinique] (MFME [Fort de France]), CHU de la Martinique [Fort de France], Koc University School of Medicine [Istanbul, Turkey] (KUSOM), and CarMeN, laboratoire
Subjects: [SDV] Life Sciences [q-bio], Loss of Function Mutation, [SDV]Life Sciences [q-bio], Vertebrates, Metalloproteases, Genetics, Animals, Humans, Proteins, Gene Regulatory Networks, Cilia, Biological Evolution, Body Patterning
Abstract: Erratum in Publisher Correction: Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. Szenker-Ravi E, Ott T, Khatoo M, Moreau de Bellaing A, Goh WX, Chong YL, Beckers A, Kannesan D, Louvel G, Anujan P, Ravi V, Bonnard C, Moutton S, Schoen P, Fradin M, Colin E, Megarbane A, Daou L, Chehab G, Di Filippo S, Rooryck C, Deleuze JF, Boland A, Arribard N, Eker R, Tohari S, Ng AY, Rio M, Lim CT, Eisenhaber B, Eisenhaber F, Venkatesh B, Amiel J, Crollius HR, Gordon CT, Gossler A, Roy S, Attie-Bitach T, Blum M, Bouvagnet P, Reversade B.Nat Genet. 2022 Jun;54(6):906. doi: 10.1038/s41588-022-01053-8.PMID: 35304595 No abstract available.; International audience; The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.
Published: 2022
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15. Copy number variants calling from WES data through eXome hidden Markov model (XHMM) identifies additional 2.5% pathogenic genomic imbalances smaller than 30 kb undetected by array-CGH

Author: Emilie Tisserant, Antonio Vitobello, Davide Callegarin, Simon Verdez, Ange‐line Bruel, Ludwig Serge Aho Glele, Arthur Sorlin, Eleonore Viora‐Dupont, Marina Konyukh, Nathalie Marle, Sophie Nambot, Sébastien Moutton, Caroline Racine, Aurore Garde, Julian Delanne, Frédéric Tran‐Mau‐Them, Christophe Philippe, Paul Kuentz, Marlène Poulleau, Muriel Payet, Charlotte Poe, Christel Thauvin‐Robinet, Laurence Faivre, Anne‐Laure Mosca‐Boidron, Julien Thevenon, Yannis Duffourd, and Patrick Callier
Subjects: Comparative Genomic Hybridization, DNA Copy Number Variations, Intellectual Disability, Exome Sequencing, Genetics, Humans, Exome, Genomics, Genetics (clinical)
Abstract: It has been estimated that Copy Number Variants (CNVs) account for 10%-20% of patients affected by Developmental Disorder (DD)/Intellectual Disability (ID). Although array comparative genomic hybridization (array-CGH) represents the gold-standard for the detection of genomic imbalances, common Agilent array-CGH 4 × 180 kb arrays fail to detect CNVs smaller than 30 kb. Whole Exome sequencing (WES) is becoming the reference application for the detection of gene variants and makes it possible also to infer genomic imbalances at single exon resolution. However, the contribution of small CNVs in DD/ID is still underinvestigated. We made use of the eXome Hidden Markov Model (XHMM) software, a tool utilized by the ExAC consortium, to detect CNVs from whole exome sequencing data, in a cohort of 200 unsolved DD/DI patients after array-CGH and WES-based single nucleotide/indel variant analyses. In five out of 200 patients (2.5%), we identified pathogenic CNV(s) smaller than 30 kb, ranging from one to six exons. They included two heterozygous deletions in TCF4 and STXBP1 and three homozygous deletions in PPT1, CLCN2, and PIGN. After reverse phenotyping, all variants were reported as causative. This study shows the interest in applying sequencing-based CNV detection, from available WES data, to reduce the diagnostic odyssey of additional patients unsolved DD/DI patients and compare the CNV-detection yield of Agilent array-CGH 4 × 180kb versus whole exome sequencing.
Published: 2021

16. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

Author: Arthur Sorlin, Antonio Vitobello, Benoit Daubail, Christel Thauvin-Robinet, Marie Hervieu-Bègue, Laurence Faivre, Agnès Fromont, Ange-Line Bruel, Frédéric Tran Mau-Them, Thibault Moreau, Julian Delanne, Guy-Victor Osseby, Quentin Thomas, Patrick Callier, Christophe Philippe, Sébastien Moutton, Maurice Giroud, Anne-Sophie Denommé-Pichon, Agnès Jacquin-Piques, Sophie Nambot, Yannis Duffourd, Philippine Garret, Y Béjot, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Neurophysiologie Clinique (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Proband, Pediatrics, medicine.medical_specialty, Movement disorders, Neurology, Neurodegeneration with brain iron accumulation, [SDV]Life Sciences [q-bio], Encephalopathy, Neurogenetics, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, Humans, Medicine, Exome, Clinical significance, 030212 general & internal medicine, Genetic Testing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Nervous System Diseases, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.
Published: 2021
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17. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Anne-Sophie Denommé, Christine Francannet, Loréline Genschik, Claire Feger, Maria Kibaek, Imene Boujelbene, Paul Kuentz, Michel Guipponi, Marie-Christine Birling, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Mathilde Renaud, Joane Svane, Yann Herault, Sandrine Passemard, Christèle Dubourg, Mélanie Fradin, Marjolaine Willems, Julien Thevenon, Rosanna Weksberg, Bertrand Isidor, David Geneviève, Benjamin Cogné, Magalie Barth, Laurence Faivre, Jérémie Courraud, Boris Keren, Albert David, Laurence Perrin, Anne-Marie Guerrot, Christine Coubes, Thierry Bienvenu, Alice Goldenberg, Bénédicte Gérard, Amélie Piton, Lucas Bronicki, Julia Metreau, Mathilde Nizon, Elise Schaefer, Eric Chater-Diehl, Maria del Mar Muniz Moreno, Bruno Delobel, Katrine M Johannesen, Florence Demurger, Nathalie Drouot, Marie Vincent, Antonio Vitobello, Kristina Pilekær Sørensen, Christina Fagerberg, Cyril Mignot, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Jean-Louis Mandel, Cathrine Elisabeth Tronhjem, Benjamin Durand, Pascale Saugier, Séverine Drunat, Rikke S. Møller, Perrine Charles, Lydie Burglen, Bénédicte Demeer, Salima El Chehadeh, Marc Abramowicz, Laurent Pasquier, and Julie D. Thompson
Subjects: Genetics, Neurodevelopmental disorder, DYRK1A, Intellectual disability, medicine, Missense mutation, Kinase activity, Biology, medicine.disease, Phenotype, Human genetics, Cellular localization
Abstract: ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurringde novo.
Published: 2021
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18. Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt

Author: Didier Lacombe, Claire Duflos, David Geneviève, Jeanne Amiel, Elodie Sanchez, Yline Capri, Damien Sanlaville, Marlène Rio, Alexandra Afenjar, Fabienne Giuliano, Elise Brischoux-Boucher, Mathilde Nizon, Stanislas Lyonnet, Sébastien Moutton, Vincent Gatinois, Stéphanie Arpin, Annick Toutain, Mouna Barat-Houari, Guilaine Boursier, Flavien Rouxel, Sophie Julia, Klaus Dieterich, Aurélia Jacquette, Boris Keren, Kevin Yauy, Patricia Blanchet, Marie-Line Jacquemont, Damien Haye, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne (UNIL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Grenoble, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), GRC ConCer-LD, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maison de Santé Protestante Bagatelle, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)
Subjects: Image Series, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Biology, [INFO.INFO-NE]Computer Science [cs]/Neural and Evolutionary Computing [cs.NE], Facial recognition system, Article, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Artificial neural network, Receiver operating characteristic, business.industry, Significant difference, Genetic disorder, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, medicine.disease, Hematologic Diseases, Vestibular Diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, Gestalt psychology, Artificial intelligence, business, Kabuki syndrome, Facial Recognition
Abstract: International audience; Kabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals.
Published: 2021
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19. PURA- Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

Author: Dario Pruna, Theresa Grebe, Felippe Borlot, Michael J. Esser, Juan Pablo Appendino, Katherine L. Helbig, Elisa Ballardini, Casey Brew, Anne-Sophie Denommé-Pichon, Anne Ronan, Laurie A. Demmer, Usha Kini, Marta Somorai, Julie Vogt, Sébastien Moutton, Raffaella Faggioli, Julien Van-Gils, Davide Ognibene, Sara Olivotto, Sabine Grønborg, David Coman, David P. Bick, Guido Rubboli, Orrin Devinsky, Atiya S. Khan, Robyn Whitney, Christine Coubes, Caroline Nava, Karen Keough, SakkuBai R. Naidu, Lucio Giordano, Davide Colavito, Dominic Spadafore, Arnaud Isapof, Walla Al-Hertani, Antonio Vitobello, Andrea V. Andrade, Gaetano Cantalupo, Sandra Whalen, Boudewijn Gunning, Shanawaz Hussain, David Hunt, Nathan Noble, Bertrand Isidor, Beatriz Gamboni, Katrine M Johannesen, Julien Buratti, Stephanie Moortgat, Ida Cursio, Agnese Suppiej, Delphine Héron, Lía Mayorga, William Benko, Rahul Raman Singh, Cyril Mignot, Sotirios Keros, Aurore Garde, Nicola Foulds, Claudia A. L. Ruivenkamp, Elena Gardella, Barbara Scelsa, Fernanda Góes, Laurence Faivre, Richard J. Leventer, Ashley Collier, Farha Tokarz, Thomas Courtin, Klaas J. Wierenga, Xilma R. Ortiz-Gonzalez, Frédéric Tran-Mau-Them, Alejandra Mampel, Lynn Greenhalgh, Ashlea Franques, Amélie Piton, Felicia Varsalone, Marjolaine Willems, Alessandro Orsini, Diana Rodriguez, Clothilde Ormieres, Helen Stewart, Boris Keren, Austin Larson, Cathrine E. Gjerulfsen, Julie S. Cohen, Margot R.F. Reijnders, Mel Anderson, Shailesh Asakar, Rikke S. Møller, Alice Bonuccelli, Alexandra Afenjar, Claudio Graziano, Elaine Wirrell, Simona Damioli, Sangeetha Yoganathan, Devorah Segal, Ingo Helbig, Mindy H. Li, Rob P.W. Rouhl, Sarah Hicks, Allan Bayat, Holly Dubbs, Stefania Bigoni, Kelly Ratke, John Brandsema, Eva H. Brilstra, univOAK, Archive ouverte, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mayo Clinic [Jacksonville], Département de pédiatrie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), and University of Colorado Anschutz [Aurora]
Subjects: Pediatrics, medicine.medical_specialty, Socio-culturale, [SDV.GEN] Life Sciences [q-bio]/Genetics, Electroencephalography, Epilepsy, Developmental and Epileptic Encephalopathy, Intellectual disability, medicine, Genetics (clinical), feeding difficulties, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, fungi, medicine.disease, Hypotonia, Epileptic spasms, Neonatal hypotonia, neonatal hypotonia, Epilepsy syndromes, Cohort, epilepsy, Neurology (clinical), medicine.symptom, business
Abstract: Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
Published: 2021
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20. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author: Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Published: 2020
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21. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author: Julien Thevenon, Sophie Blesson, Sylvie Manouvrier Hanu, Chloé Quélin, Florence Fellmann, Nicolas Chassaing, Fabienne Giuliano, Laetitia Lambert, Caroline Rooryck-Thambo, Pierre-Simon Jouk, Sylvie Di Filippo, Alexandre Vasiljevic, Christine Francannet, Daphné Lehalle, Audrey Putoux, Anna‐Gaëlle Giguet‐Valard, Sophie Naudion, Salima El Chehadeh, Estelle Colin, Viorica Ciorna‐Monferrato, Bruno Reversade, Lionel Van Maldergem, Fanny Morice-Picard, Renaud Touraine, Sébastien Moutton, Jocelyne Attia, Laurent Pasquier, A. Vigouroux-Castera, Catherine Yardin, Tania Attié-Bitach, Carine Abel, Hui Liu, Sylvie Odent, Christelle Cabrol, Florence Petit, Philippe Khau Van Kien, Thomas Simonet, Catherine Vincent-Delorme, Jean Chiesa, Juliette Piard, Anne Bazin, Mélanie Fradin, Bertrand Isidor, Loubna El Zein, Patrice Bouvagnet, Marie-Pierre Brechard, Emmanuelle Szenker-Ravi, Sophie Scheidecker, Claire Beneteau, and ACS - Heart failure & arrhythmias
Subjects: Heart Defects, Congenital, Male, midline anomaly, Heterozygote, medicine.medical_specialty, Genetic counseling, Consanguinity, Heterotaxy Syndrome, Biology, DNA sequencing, 03 medical and health sciences, consanguinity, Genetics, medicine, Humans, Family, Family history, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, Obstetrics, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, heterotaxy, congenital heart defects, Cardiac malformations, Pedigree, fetus, Parental consanguinity, Cytogenetic Analysis, Mutation, Female, next-generation sequencing, Heterotaxy
Abstract: Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.
Published: 2020

22. Publisher Correction: Discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates

Author: Emmanuelle Szenker-Ravi, Tim Ott, Muznah Khatoo, Anne Moreau de Bellaing, Wei Xuan Goh, Yan Ling Chong, Anja Beckers, Darshini Kannesan, Guillaume Louvel, Priyanka Anujan, Vydianathan Ravi, Carine Bonnard, Sébastien Moutton, Patric Schoen, Mélanie Fradin, Estelle Colin, André Megarbane, Linda Daou, Ghassan Chehab, Sylvie Di Filippo, Caroline Rooryck, Jean-François Deleuze, Anne Boland, Nicolas Arribard, Rukiye Eker, Sumanty Tohari, Alvin Yu-Jin Ng, Marlène Rio, Chun Teck Lim, Birgit Eisenhaber, Frank Eisenhaber, Byrappa Venkatesh, Jeanne Amiel, Hugues Roest Crollius, Christopher T. Gordon, Achim Gossler, Sudipto Roy, Tania Attie-Bitach, Martin Blum, Patrice Bouvagnet, and Bruno Reversade
Subjects: Genetics
Published: 2022
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23. Clinical and Molecular Spectrum of Nonsyndromic Early‐Onset Osteoarthritis

Author: Geneviève Baujat, Didier Lacombe, Marjolaine Willems, Aurélie Fabre, Sabine Sigaudy, Florence Apparailly, Isabelle Touitou, Sébastien Moutton, Bertrand Isidor, Mouna Barat-Houari, Mélanie Fradin, Julien Van-Gils, David Geneviève, Patricia Blanchet, Valentin Ruault, Christian Jorgensen, Chloé Angelini, Kevin Yauy, Silvestre Cuinat, Elodie Sanchez, Sylvie Odent, Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), SeqOne [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Hôpital de la Timone [CHU - APHM] (TIMONE), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and APPARAILLY, Florence
Subjects: Male, medicine.medical_specialty, Adolescent, Joint replacement, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Population, Osteoarthritis, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Immunology and Allergy, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Aggrecans, Age of Onset, education, Collagen Type II, 030304 developmental biology, 2. Zero hunger, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 0303 health sciences, education.field_of_study, Genetic heterogeneity, business.industry, medicine.disease, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sulfate Transporters, Joint pain, Etiology, Disease Progression, Female, Age of onset, medicine.symptom, business, Body mass index
Abstract: International audience; Objective. Osteoarthritis (OA) is the most common joint disease worldwide. The etiology of OA is varied, ranging from multifactorial to environmental to monogenic. In a condition called early-onset OA, OA occurs at an earlier age than is typical in the general population. To our knowledge, there have been no large-scale genetic studies of individuals with early-onset OA. The present study was undertaken to investigate causes of monogenic OA in individuals with nonsyndromic early-onset OA.Methods. The study probands were 45 patients with nonsyndromic early-onset OA who were referred to our skeletal disease center by skeletal dysplasia experts between 2013 and 2019. Criteria for early-onset OA included radiographic evidence, body mass index ≤30 kg/m 2 , age at onset ≤50 years, and involvement of ≥1 joint site. Molecular analysis was performed with a next-generation sequencing panel Results. We identified a genetic variant in 13 probands (29%); the affected gene was COL2A1 in 11, ACAN in 1, and SLC26A2 in 1. After familial segregation analysis, 20 additional individuals were identified. The mean ± SD age at onset of joint pain was 19.5 ± 3.9 years (95% confidence interval 3-47). Eighteen of 33 subjects (55%) with nonsyndromic early-onset OA and a genetic variant had had at least 1 joint replacement (mean ± SD age at first joint replacement 41 ± 4.2 years; mean number of joint replacements 2.6 per individual), and 21 (45%) of the joint replacement surgeries were performed when the patient was 40 years, 17 (85%) had had at least 1 joint replacement.Conclusion. We confirmed that COL2A1 is the main monogenic cause of nonsyndromic early-onset OA. However, on the basis of genetic heterogeneity of early-onset OA, we recommend next-generation sequencing for all individuals who undergo joint replacement prior to the age of 45 years. Lifestyle recommendations for prevention should be implemented. ClinicalTrials.gov identifier: NCT04267510.
Published: 2020
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24. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

Author: Paul Kruszka, Sreehari Kalvakuri, Austin Larson, Dong Li, Inge van Outersterp, Florence Demurger, Ian Hayes, F. Lucy Raymond, Lauren J. Massingham, Claudia A. L. Ruivenkamp, Ian D. Krantz, Kendra Brunet, Nicole Revencu, Maaike Vreeburg, Donatella Milani, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Maximilian Muenke, Sinje Geuer, Candace Gamble, Rolf Bodmer, Hanka Venselaar, Elke de Boer, Sarina G. Kant, Dilys Weijers, Arjan P.M. de Brouwer, Machteld M. Oud, Maria Iascone, Christopher C. Griffith, Frédéric Tran Mau-Them, Karin Weiss, Megan T. Cho, Ayesha Ahmad, James A. Bartley, Nina Powell Hamilton, Lenika De Simone, George E. Hoganson, Lucie Evenepoel, Simone Kersten, Daniel L. Polla, Himanshu Goel, Antonio Vitobello, Rachel Fisher, Arthur Sorlin, Sébastien Moutton, Myrthe van den Born, Hilary J. Vernon, Michael Kwint, Kaitlyn Burns, Anna Ruiz, Kirsty McWalter, Jenny Morton, Jennifer Schwab, Elizabeth J. Bhoj, Philippe Christophe, Hans van Bokhoven, Elisabeth Gabau, Kimberly M. Nugent, Jill R. Murrell, Thierry Billette de Villemeur, Kathleen Wood, Alexandra Afenjar, Amber Begtrup, Chanika Phornphutkul, Sarah E. Raible, Melde Witmond, Perrine Charles, Claudia Soler-Alfonso, D. Isum Ward, Marjolaine Willems, Boris Keren, Julian Delanne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Polikliniek (9)
Subjects: Male, DYRK1A, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gene Expression, de novo mutations, Haploinsufficiency, 0302 clinical medicine, Gene expression, Nuclear Receptor Subfamily 4, Group A, Member 2, Genetics (clinical), Genetics, 0303 health sciences, Gene knockdown, repressor, neurodevelopment, Protein Stability, CCR4-NOT complex, Phenotype, developmental delay, intellectual disability, Drosophila, deadenylase complex, Female, regulators, Heterozygote, Receptors, CCR4, Biology, Nervous System Malformations, 03 medical and health sciences, Report, genomics, Humans, Gene, Alleles, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, Protein ubiquitination, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Neurodevelopmental Disorders, SUBUNIT, RNA, CNOT1, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], exome sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access) CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
Published: 2020

25. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome

Author: Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, Sara El Kennani, Joaquim Sá, Karen J. Low, Cristina Dias, Markéta Havlovicová, Miroslava Hančárová, Evan E. Eichler, Françoise Devillard, Sébastien Moutton, Julien Van-Gils, Christèle Dubourg, Sylvie Odent, Bénédicte Gerard, Amélie Piton, Toshiyuki Yamamoto, Nobuhiko Okamoto, Helen Firth, Kay Metcalfe, Anna Moh, Kimberly A. Chapman, Erfan Aref-Eshghi, Jennifer Kerkhof, Annalaura Torella, Vincenzo Nigro, Laurence Perrin, Juliette Piard, Gwenaël Le Guyader, Thibaud Jouan, Christel Thauvin-Robinet, Yannis Duffourd, Jaya K. George-Abraham, Catherine A. Buchanan, Denise Williams, Usha Kini, Kate Wilson, Nicola Brunetti-Pierri, Giorgio Casari, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Sérgio B. Sousa, Raoul C.M. Hennekam, Bekim Sadikovic, Julien Thevenon, Jérôme Govin, Antonio Vitobello, Università degli studi di Napoli Federico II, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Washington [Seattle], Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bordeaux (UB), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), London Health Sciences Center (LHSC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), GSP15001, Fondazione Telethon, 209568/Z/17/Z, Wellcome Trust, Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, General Paediatrics, APH - Quality of Care, and Brunetti-Pierri, Nicola
Subjects: Foot Deformities, Foot Deformities, Congenital, [SDV]Life Sciences [q-bio], Biology, Blepharophimosis, Settore MED/03 - GENETICA MEDICA, Hypotrichosis, Chromatin remodeling, 03 medical and health sciences, Congenital, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, SMARCA2, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, BIS, Facies, medicine.disease, Phenotype, neurodevelopmental disorder, Nicolaides–Baraitser syndrome, intellectual disability, DNA methylation, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
Published: 2020
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26. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders

Author: Marcie A. Steeves, Marjorlaine Willems, Siddharth Banka, Yline Capri, Michael J. Parker, Stephanie Greville-Heygate, Emma Clement, David Goudie, Vincent Cantagrel, Diana Rodriguez, Marlène Rio, Matthew Guille, Htoo A Wai, Anne Debant, Ajoy Sarkar, Fleur Vansenne, Frédéric Tran Mau-Them, Peter D Turnpenny, Audrey Putoux, Christine Fagotto-Kaufmann, Karine Siquier-Pernet, Bert B.A. de Vries, Boris Keren, Maxime Bonnet, Lydie Burglen, Sébastien Moutton, Marion Gérard, Susanne Schmidt, Diana Baralle, Sónia Barbosa, Benjamin Cogné, Damien Laouteouet, Amélie Piton, Helen Cox, Rebecca Mawby, Marie Vincent, Annie Godwin, Andrey V. Kajava, Sarju G. Mehta, Alexander J. M. Dingemans, Jozef Hertecant, Jayne Y. Hehir-Kwa, Gaetan Lesca, Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: Male, rac1 GTP-Binding Protein, 0301 basic medicine, Microcephaly, INTELLECTUAL DISABILITY, [SDV]Life Sciences [q-bio], APC-PAID, medicine.disease_cause, Cohort Studies, PATHWAY, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, Missense mutation, Spectrin, microcephaly, GEF, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, Mutation, Spectrin repeat, Phenotype, intellectual disability, BBSRC, Female, Nonsense mutation, autism, Protein Serine-Threonine Kinases, Biology, macrocephaly, RHO-GTPASES, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Humans, Amino Acid Sequence, BB/R014841/1, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Sequence Homology, Amino Acid, RCUK, medicine.disease, HEK293 Cells, 030104 developmental biology, XENOPUS, Neurodevelopmental Disorders, Axon guidance, 030217 neurology & neurosurgery, SPERM
Abstract: The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
Published: 2020
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27. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Author: Florence Petit, Clémence Vanlerberghe, Thomas Smol, Fabienne Giuliano, M.F. Odou, Sylvie Manouvrier-Hanu, Perrine Brunelle, William Dufour, Malika Balduyck, Fabienne Escande, Jamal Ghoumid, Marion Gérard, Philippe Khau Van Kien, Gilles Morin, Cindy Colson, Alice Goldenberg, Elise Brischoux-Boucher, Anne Dieux, Daphné Lehalle, Anne-Sophie Jourdain, Sébastien Moutton, Simon Boussion, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Laboratoire Pierre Süe (LPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Inserm, Université de Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Maladies RAres du DÉveloppement embryonnaire et du Métabolisme : du phénotype au génotype et à la Fonction (RADEME) - ULR 7364, CIC CHU ( Lille)/inserm, Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Service de Génétique Clinique [CHU Caen], Université de Lausanne = University of Lausanne [UNIL], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME], and Richard, Nicolas
Subjects: Male, Candidate gene, limb malformation, molecular diagnosis, targeted high-throughput sequencing, genetics, DNA Copy Number Variations, DNA Mutational Analysis, Limb Deformities, Congenital, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, DNA sequencing, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Multiplex, Genetic Testing, Uncertain significance, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Likely pathogenic, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Phenotype, 3. Good health, Radiography, Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female
Abstract: International audience; Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
Published: 2020
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28. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author: Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric
Subjects: 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract: PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online
Published: 2020
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29. Growth charts in Kabuki syndrome 1

Author: Claire Jeandel, Caroline Michot, Odile Boute, Mario Abaji, Stanislas Lyonnet, Julie Reversat, Lucile Pinson, Sandrine Akouete, Bertrand Isidor, Marie-Ange Delrue, Valérie Cormier-Daire, Isabelle Touitou, Pierre Sarda, Bérénice Doray, Tiffany Busa, Anne Moncla, Véra Georgescu, Alice Goldenberg, Damien Sanlaville, Cyril Amouroux, Elodie Sanchez, Mélanie Fradin, Guilaine Boursier, Didier Lacombe, Mouna Barat-Houari, Annick Toutain, Brigitte Gilbert-Dussardier, David Geneviève, Fabienne Giuliano, Kim Hanh Le Quan Sang, Joelle Roume, Marianne Till, Yves Alembick, Nicole Philip, Elise Schaefer, Marjolaine Willems, Claire Duflos, Aurélia Jacquette, Eudeline Alix, Sébastien Moutton, Adeline Bonnard, Vincent Gatinois, Marie-Pierre Cordier, Clarisse Baumann, Martine Le Merrer, Marie-Line Jacquemont, Lydie Burglen, Valentin Ruault, Laurence Faivre, Carole Corsini, Sylvie Manouvrier, Svetlana Gorokhova, Anna Pelet, Delphine Héron, Sylvie Odent, Jeanne Amiel, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département d'Information Médicale [CHRU Montpellier], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital saint Pierre, GH Sud Réunion, Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Salvy-Córdoba, Nathalie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]
Subjects: Male, MESH: Neoplasm Proteins, CHILDREN, Growth, MESH: Growth Charts, Body Mass Index, MALFORMATION, Parental target size, MESH: Child, KDM6A, Growth Charts, Child, Specific curves, Genetics (clinical), 2. Zero hunger, Genetics & Heredity, Histone Demethylases, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Increase size, Circumference, MESH: Hematologic Diseases, Adult height, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Child, Preschool, Cohort, MLL2, Female, MESH: Vestibular Diseases, Life Sciences & Biomedicine, MESH: Face, growth hormone deficiency, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, growth, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Growth hormone deficiency, MESH: Body Mass Index, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, EARS, MESH: Body Height, MESH: Histone Demethylases, Genetics, medicine, Humans, Abnormalities, Multiple, education, 030304 developmental biology, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Science & Technology, Kabuki syndrome, MESH: Humans, business.industry, MUTATIONS, Body Weight, MESH: Child, Preschool, specific curves, MAKE-UP-SYNDROME, medicine.disease, Hematologic Diseases, Body Height, MESH: Male, MESH: Body Weight, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parental target size, Face, Mutation, business, Body mass index, MESH: Female, MESH: DNA-Binding Proteins, Demography
Abstract: Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size. ispartof: AMERICAN JOURNAL OF MEDICAL GENETICS PART A vol:182 issue:3 pages:446-453 ispartof: location:United States status: published
Published: 2019
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30. Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

Author: Alica M. Goldman, Frédéric Tran Mau-Them, Bertrand Isidor, Francesca Mattioli, Gaëlle Hayot, Piton Amélie, Jérémie Courraud, Jamel Chelly, Sarah Grotto, Ganka Douglas, Aida Telegrafi, Alicia Boughton, Sébastien Moutton, Mandel Jean-Louis, Christelle Golzio, Zohra Shad, Nathalie Drouot, Chantal Sellier, Yue Cindy Si, Elisabeth Kaplan, Sophie Nambot, Nolwenn Jean, Paul C. Van Ness, Candace Gamble, Angélique Quartier, Nicolas Charlet, Richard Dineen, and Maria-Victoria Hinckelmann
Subjects: Genetics, 0303 health sciences, Ataxia, NOVA2 Gene, Alternative splicing, Biology, Hypotonia, Frameshift mutation, 03 medical and health sciences, Splicing factor, 0302 clinical medicine, RNA splicing, medicine, medicine.symptom, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.
Published: 2019
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31. OC18.02: Exome sequencing during pregnancy for fetuses with unsolved multiple congenital abnormalities: a powerful tool to improve prenatal diagnosis

Author: Arthur Sorlin, Ange-Line Bruel, Julian Delanne, Mathilde Lefebvre, Sébastien Moutton, Christel Thauvin, Antonio Vitobello, F. Tran Mau Them, Aurore Garde, and N. Bourgon
Subjects: Fetus, medicine.medical_specialty, Pregnancy, Radiological and Ultrasound Technology, Obstetrics, business.industry, Obstetrics and Gynecology, Prenatal diagnosis, General Medicine, medicine.disease, Reproductive Medicine, medicine, Radiology, Nuclear Medicine and imaging, business, Exome sequencing
Published: 2021
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32. 19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference

Author: Vanna Pecile, Didier Lacombe, Antonella Fabretto, Cécile Boucher, Clémence Vanlerberghe, Benoit Arveiler, Emma L. Baple, Nada Houcinat, Kate Robertshaw, Patricia Fergelot, Gemma Poke, Bruno Delobel, Aurélien Trimouille, Colina McKeown, Joris Andrieux, Paolo Gasparini, Bénédicte Duban, Jérôme Toutain, Marco Carrozzi, Mathilde Nizon, Sébastien Moutton, Marie Vincent, Sahar Mansour, Cédric Le Caignec, Caroline Rooryck, Eve Fifield, Marie Laure Vuillaume, Trimouille, Aurélien, Houcinat, Nada, Vuillaume, Marie-Laure, Fergelot, Patricia, Boucher, Cécile, Toutain, Jérôme, Caignec, Cédric Le, Vincent, Marie, Nizon, Mathilde, Andrieux, Jori, Vanlerberghe, Clémence, Delobel, Bruno, Duban, Bénédicte, Mansour, Sahar, Baple, Emma, Mckeown, Colina, Poke, Gemma, Robertshaw, Kate, Fifield, Eve, Fabretto, Antonella, Pecile, Vanna, Gasparini, Paolo, Carrozzi, Marco, Lacombe, Didier, Arveiler, Benoît, Rooryck, Caroline, and Moutton, Sébastien
Subjects: Male, 0301 basic medicine, Adolescent, Genetics, Genetics (clinical), Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Intellectual Disability, Chromosome Duplication, Gene duplication, Intellectual disability, medicine, Humans, Abnormalities, Multiple, Copy-number variation, Child, biology, Sotos syndrome, Macrocephaly, Infant, Syndrome, medicine.disease, NFIX, NFI Transcription Factors, 030104 developmental biology, Child, Preschool, Chromosomal region, biology.protein, Female, medicine.symptom, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract: Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.
Published: 2017
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33. STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability

Author: Julien Thevenon, Christiane Zweier, Hilde Olivié, Nicole Revencu, Aurélia Jacquette, Megan T. Cho, Anne-Laure Mosca-Boidron, Marjolein H. Willemsen, Laurence Faivre, Yannis Duffourd, Odile Boute-Benejean, Elaine H. Zackai, Carey McDougall, Amber Begtrup, Anita Rauch, Christel Thauvin-Robinet, Perrine Charles, Koen L.I. van Gassen, Thomas Smol, Laurence Duplomb-Jego, Daphné Lehalle, Amanda Clarkson, Orrin Devinsky, Catherine Vincent-Delorme, Paul Kuentz, Bénédicte Gérard, Patrick Callier, Karol Rubin, Jean-Baptiste Rivière, Sébastien Moutton, Deborah J. Shears, Ana Lisa Taylor Tavares, Ingrid Simonic, Paulien A. Terhal, Soo-Mi Park, Alice Masurel-Paulet, and Golder N. Wilson
Subjects: 0301 basic medicine, Genetics, Mutation, Cohesin complex, Point mutation, Biology, medicine.disease, medicine.disease_cause, Bioinformatics, Frameshift mutation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Intellectual disability, medicine, Journal Article, Missense mutation, Gene, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Item does not contain fulltext BACKGROUND: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations. METHODS: Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards. RESULTS: A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy. CONCLUSIONS: We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.
Published: 2017
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34. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

Author: Florence Demurger, Christine Binquet, Muriel Holder, Frédéric Tran Mau-Them, Salima El Chehadeh, Martine Doco-Fenzy, Geneviève Baujat, Delphine Héron, Judith St-Onge, Christophe Philippe, Elodie Gautier, Robert Olaso, Rebecca A. Barnard, Paul Kuentz, François Lecoquierre, Stanislas Lyonnet, Gwenaëlle Collod-Béroud, Dominique Martin-Coignard, Isabelle Missotte, Anne Boland, Cyril Goizet, Laurence Perrin, Valérie Cormier-Daire, Sébastien Moutton, Nadine Hanna, Jean-François Deleuze, Audrey Putoux, Guillaume Jondeau, Sylvie Odent, Doris Lechner, Arnold Munnich, Thibaud Jouan, Aurélia Jacquette, Pierre-Simon Jouk, Martin Chevarin, Virginie Carmignac, Elisabetta Lapi, Alice Goldenberg, Christel Thauvin-Robinet, Sujatha Jagadeesh, P. Callier, Fatma Daoud, Yannis Duffourd, Frédéric Huet, Nathalie Marle, Charlotte Poe, Gipsy Lopez, Cyril Mignot, Florence Petit, Khadija Amarof, Brian J. O'Roak, Caroline Cabret, Fanny Morice-Picard, Jean Baptiste Rivière, Mirna Assoum, Marie Ange Delrue, Julien Thevenon, Laurence Faivre, David Geneviève, Elisabeth Sarrazin, Ange Line Bruel, Pauline Arnaud, Catherine Boileau, Christine Coubes, Didier Lacombe, Laurence Duplomb, Alice Masurel, Patrick Collignon, Antonio Vitobello, Julien Van-Gils, Bruno Leheup, Nolwenn Jean-Marçais, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Le Mans (CH Le Mans), CHU Pitié-Salpêtrière [AP-HP], Hôpital Robert Debré Paris, Hôpital Robert Debré, Hospices Civils de Lyon (HCL), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], Centre hospitalier territorial Gaston-Bourret [Nouméa], CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Proband, Male, [SDV]Life Sciences [q-bio], intellectual deficiency, MESH: NFI Transcription Factors, chromatin remodeling, Marfan Syndrome, Craniofacial Abnormalities, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Mental Retardation, X-Linked, Exome, Child, de novo variants, Genetics (clinical), Exome sequencing, Genetics, MESH: Exome, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, NFIX, MESH: Young Adult, Female, Adult, MESH: Mutation, Adolescent, Chromatin remodeling, MESH: Intellectual Disability, MESH: Marfan Syndrome, EHMT1, Young Adult, MESH: Whole Exome Sequencing, Intellectual Disability, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, marfanoid habitus, Gene, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, Genetic heterogeneity, MESH: Chromatin Assembly and Disassembly, MESH: Histone-Lysine N-Methyltransferase, MESH: Adult, Histone-Lysine N-Methyltransferase, medicine.disease, Chromatin Assembly and Disassembly, MESH: Male, NFI Transcription Factors, Neurodevelopmental Disorders, Mutation, biology.protein, Mental Retardation, X-Linked, MESH: Female
Abstract: PurposeMarfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.MethodsTo further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.ResultsWe identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.ConclusionWe demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
Published: 2019
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35. Clinical study of 19 patients with SCN 8A ‐related epilepsy: Two modes of onset regarding EEG and seizures

Author: Svetlana Gataullina, Cécile Mignon-Ravix, Julien Denis, Frédéric Villega, Cecilia Altuzarra, Melanie Martin, Magalie Barth, Jean-Michel Pedespan, Sophie Julia, Alexandra Afenjar, Laurent Villard, Nathalie Villeneuve, Laurence Lion-François, Sophie Gueden, Diane Doummar, Jeremie Lefranc, Mathieu Milh, Pierre Cacciagli, Caroline Lacoste, Claude Cances, Lena Damaj, Cyril Mignot, Sébastien Moutton, Hubert Journel, Bruria Ben Zeev, Olivier Dulac, Sylvia Napuri, Gaetan Lesca, Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsie et ischémie cérébrale, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de pédiatrie, hôpital Sud, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], CHU Bordeaux [Bordeaux], Service de Génétique Médicale du CHU de Bordeaux, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pédiatrie [CHU Toulouse], CHU Toulouse [Toulouse], Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Pediatrics, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Tel Aviv University [Tel Aviv], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Sud, CHU Pitié-Salpêtrière [APHP], Service de neuropédiatrie [Trousseau], Centre Hospitalier Bretagne Atlantique [Vannes], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Tel Aviv University (TAU)
Subjects: Male, 0301 basic medicine, Pediatrics, Delayed Diagnosis, Movement disorders, [SDV]Life Sciences [q-bio], Electroencephalography, Epilepsy, 0302 clinical medicine, Pregnancy, Prospective Studies, Age of Onset, Fetal Movement, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, Seizure types, Normal interictal EEG, 3. Good health, Epileptic spasms, Phenotype, Neurology, Cohort, Anticonvulsants, Female, medicine.symptom, Sodium Channel Blockers, medicine.medical_specialty, Myoclonic Jerk, Mutation, Missense, 03 medical and health sciences, Munc18 Proteins, Seizures, medicine, Humans, KCNQ2 Potassium Channel, business.industry, Infant, Newborn, Infant, medicine.disease, Early Diagnosis, 030104 developmental biology, Amino Acid Substitution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NAV1.6 Voltage-Gated Sodium Channel, Neurology (clinical), business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Objective To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. Methods We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. Results We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. Significance SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.
Published: 2019
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36. Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders

Author: Brigitte Gilbert-Dussardier, Patrick Edery, Flavie Diguet, Géraldine Joly-Hélas, Fanny Morice-Picard, Nicolas Chatron, Jeanne Amiel, Fabienne Prieur, Jérome Toutain, Sandra Whalen, Marine Lebrun, Gwenaël Nadeau, Sylvie Jaillard, Céline Pebrel-Richard, Annabelle Chaussenot, Bénédicte Demeer, Florence Demurger, Sophie Dupuis-Girod, Marianne Till, Nicole Philip, Jacques Puechberty, Laurent Pasquier, Pierre-Antoine Rollat-Farnier, Claire Bardel, Anne-Marie Guerrot, Anne-Claude Tabet, Sylvie Odent, Annick Toutain, Alain Verloes, Jean-Michel Dupont, Christine Coubes, Aziza Lebbar, Yline Capri, Bertrand Isidor, James Lespinasse, Didier Lacombe, Julie Masson, Sophie Blesson, Marine Houlier, Véronique Paquis-Flucklinger, Michèle Mathieu-Dramard, Florence Amblard, Patrick Callier, Jonathan Levy, Chantal Missirian, Véronique Satre, Marie-France Portnoï, Cyril Mignot, Stéphanie Valence, Catherine Sarret, Sébastien Moutton, Françoise Devillard, Alice Masurel-Paulet, Caroline Schluth-Bolard, Patrick Collignon, Jean-Pierre Siffroi, Marie-Pierre Cordier, Renaud Touraine, Marlène Rio, Céline Dupont, Cédric Le Caignec, Damien Sanlaville, Audrey Putoux, Morgane Plutino, Valérie Kremer, Valérie Malan, Martine Doco-Fenzy, Alexandra Afenjar, Caroline Rooryck-Thambo, Massimiliano Rossi, Linda Pons, Gaetan Lesca, Laurence Faivre, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de Génétique Médicale, Centre Hospitalier Intercommunal, Toulon, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique médicale, CHU Amiens-Picardie, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Pôle Couple-Enfant, Département de Génétique et Procréation, Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Service de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, CHU Rouen, Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Université de Bordeaux (UB), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Université de Lyon, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, École normale supérieure - Rennes (ENS Rennes), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Cytogénétique, Centre hospitalier de Valence, CHU Clermont-Ferrand, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Dept of Immunology, Genetics and Pathology, Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie pédiatrique [CHU Necker], CHU Bordeaux [Bordeaux], Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique, CHU Saint-Etienne-Hôpital nord, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), French National Agency for Research, French Ministry of Health, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de recherche en neurosciences de Lyon (CRNL), Université Nice Sophia Antipolis (... - 2019) (UNS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Adult, Male, 0301 basic medicine, Candidate gene, Adolescent, DNA Copy Number Variations, Developmental Disabilities, 030105 genetics & heredity, Genome, Translocation, Genetic, Structural variation, Chromosome Breakpoints, Structure-Activity Relationship, Young Adult, 03 medical and health sciences, symbols.namesake, position effect, Genetics, Humans, Child, Gene, Genetic Association Studies, Genetics (clinical), Paired-end tag, ComputingMilieux_MISCELLANEOUS, chromosomal rearrangements, Chromosome Aberrations, Gene Rearrangement, Whole genome sequencing, Sanger sequencing, whole genome sequencing, biology, structural variation, Infant, NFIX, Phenotype, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Child, Preschool, biology.protein, symbols, Female, Biomarkers
Abstract: BackgroundBalanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies.MethodsBreakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA.ResultsAmong the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation.ConclusionPaired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.
Published: 2019
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37. Autism and developmental disability caused by KCNQ3 gain-of-function variants

Author: Kavita Thakkar, François Rivier, Bitten Schönewolf-Greulich, Gaetan Lesca, Christine Francannet, Nicholas Stong, Sarah Weckhuysen, Vandana Shashi, Marjolaine Willems, Zeynep Tümer, David Goldstein, Daniel K. Arrington, Eric H. Kossoff, Anita E. Beck, Maria Virginia Soldovieri, Erin L. Heinzen, Edward C. Cooper, A. James Barkovich, Heather C Mefford, Francesco Miceli, Lynette G. Sadleir, Tristan T. Sands, Anna Lauritano, Amber Stocco, Ingrid E. Scheffer, Anne Marie Bisgaard, Ana Grijalvo Perez, Deepa S. Rajan, M. Roberta Cilio, Piera Nappi, Bénédicte Gérard, Sébastien Moutton, Maurizio Taglialatela, Antonio Vitobello, Jennifer A. Sullivan, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Sands, T. T., Miceli, F., Lesca, G., Beck, A. E., Sadleir, L. G., Arrington, D. K., Schonewolf-Greulich, B., Moutton, S., Lauritano, A., Nappi, P., Soldovieri, M. V., Scheffer, I. E., Mefford, H. C., Stong, N., Heinzen, E. L., Goldstein, D. B., Perez, A. G., Kossoff, E. H., Stocco, A., Sullivan, J. A., Shashi, V., Gerard, B., Francannet, C., Bisgaard, A. -M., Tumer, Z., Willems, M., Rivier, F., Vitobello, A., Thakkar, K., Rajan, D. S., Barkovich, A. J., Weckhuysen, S., Cooper, E. C., Taglialatela, M., Cilio, M. R., Columbia University Medical Center (CUMC), Columbia University [New York], 'Federico II' University of Naples Medical School, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Washington, Seattle, WA, USA., University of Otago [Dunedin, Nouvelle-Zélande], St. Luke's Children's Hospital, Department of Paediatrics and Adolescent Medicine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Neuroscience, University of Naples 'Federico II,' Naples, Italy., University of Molise, Epilepsy Research Centre, University of Melbourne, University of Washington, Columbia University Irving Medical Center (CUIMC), University of California [San Francisco] (UCSF), University of California, Johns Hopkins University School of Medicine [Baltimore], INTEGRIS Baptist Medical Center, School of Irish, Celtic Studies, Irish Folklore and Linguistics, University College Dublin [Dublin] (UCD), Duke University [Durham], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Clinical genetic clinic, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Hospices Civils de Lyon (HCL), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Antwerp, Antwerp, Belgium., Baylor College of Medecine, Section of Pharmacology, Università degli studi di Napoli Federico II, University of Naples 'Federico II,', University of Louvain, MORNET, Dominique, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi del Molise = University of Molise (UNIMOL), Department of Pediatrics [Seattle], University of California [San Francisco] (UC San Francisco), University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, University of Antwerp (UA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Developmental Disabilities, [SDV]Life Sciences [q-bio], Encephalopathy, Electroencephalography, Protein Structure, Secondary, KCNQ3 Potassium Channel, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, medicine, Humans, Global developmental delay, Amino Acid Sequence, Young adult, Autistic Disorder, Child, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, business.industry, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Clinical research, Neurology, Autism spectrum disorder, Child, Preschool, Gain of Function Mutation, Autism, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract: Objective Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Results Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Interpretation Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192
Published: 2019
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38. Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers

Author: Bruno Buecher, Christine Maugard, Janet Hall, Marc Fresnay, Marion Gauthier-Villars, Sébastien Moutton, Sylvain Baulande, Anne Vincent-Salomon, Laurence Gladieff, Olivier Caron, Noura Mebirouk, Pascaline Berthet, Philippe La Rosa, Georgia Chenevix-Trench, Séverine Eon-Marchais, Laetitia Fuhrmann, Anthony Laugé, Laurence Faivre, Tatiana Popova, Fabienne Lesueur, Nicolas Janin, Nadine Andrieu, Ivan Bièche, Jacques-Olivier Bay, Isabelle Coupier, Catherine Dubois d'Enghien, Juana Beauvallet, Marie-Gabrielle Dondon, Sophie Lejeune, Walid Chemlali, Dorothée Le Gal, Anne Laure Renault, Laurence Venat-Bouvet, Elodie Girard, Dominique Stoppa-Lyonnet, Paul Gesta, Jean-Pierre Fricker, Virginie Raynal, Eve Cavaciuti, Martine Labbé, Guillaume Bataillon, Hélène Zattara, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: 0301 basic medicine, Genome instability, Male, DNA Repair, Genetic instability, Loss of Heterozygosity, Ataxia Telangiectasia Mutated Proteins, Germline, Loss of heterozygosity, OncoScan array, 0302 clinical medicine, Pathology, Genomic signature, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, medicine.diagnostic_test, Copy number, BRCA1 Protein, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Genomics, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Female, SNP array, Research Article, Adult, Breast Neoplasms, Biology, lcsh:RC254-282, Breast Neoplasms, Male, 03 medical and health sciences, Ataxia Telangiectasia, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Genetic testing, Aged, BRCA2 Protein, medicine.disease, 030104 developmental biology, ATM, Ataxia-telangiectasia, Cancer research, Breast tumour, DNA Damage
Abstract: Background The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. Methods To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. Results We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22–23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially ‘druggable’ genes that would allow patients to be directed towards tailored therapeutic strategies. Conclusions Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies. Electronic supplementary material The online version of this article (10.1186/s13058-018-0951-9) contains supplementary material, which is available to authorized users.
Published: 2018
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39. Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey

Author: Jeanne Amiel, Sophie Julia, Catherine Vincent-Delorme, Christel Thauvin-Robinet, Paul Kuentz, Salima El Chehadeh, Stanislas Lyonnet, Bruno Leheup, Elodie Gautier, Odile Boute-Benejean, Nathalie Le Meur, Sandrine Marlin, Irène François, Delphine Héron, Marianne Till, Patrick Edery, Houda Karmous Benailly, Serge Romana, Nicole Philip, Patrick Callier, Valérie Cormier-Daire, Bénédicte Héron, Adeline Vigouroux-Castera, Mathilde Lefebvre, Chantal Missirian, Sylvie Odent, Fanny Morice-Picard, Roseline Caumes, Dominique Martin, Cédric Le Caignec, Nicolas Chassaing, Claire Benneteau, Anne-Laure Mosca-Boidron, Claude Ferrec, Anne-Marie Guerrot, Sylvie Manouvrier-Hanu, Eva Piparas, Damien Sanlaville, Florence Petit, Stéphanie Arpin, Sébastien Moutton, Marie-Pierre Alex-Cordier, Elodie Cretin, Laurence Faivre, Sabine Sigaudy, Tiffany Busa, Brigitte Gilbert-Dussardier, Sandra Chantot-Bastaraud, Julien Thevenon, Alexandra Afenjar, Annick Toutain, Boris Keren, Anne Philippe, Valérie Malan, Laetitia Lambert, Sandra Mercier, Elise Schaefer, James Lespinasse, Nathalie Marle, Sylvia Redon, Fabienne Giuliano, Isabelle Mortemousque, Philippe Khau Van Kien, Pierre Bitoun, Alice Goldenberg, Sophie Blesson, and Michèle Marti-Dramard
Subjects: 0301 basic medicine, Genetics, medicine.medical_specialty, education.field_of_study, Ethical issues, business.industry, Genetic counseling, Population, Retrospective cohort study, 030105 genetics & heredity, medicine.disease, Penetrance, 3. Good health, 03 medical and health sciences, Generalization (learning), Family medicine, Intellectual disability, Medicine, business, education, Genetics (clinical), Comparative genomic hybridization
Abstract: Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
Published: 2016
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40. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author: Paul R. Mark, Helena Ahlfors, Lisa Ewans, Ganka Douglas, Zornitza Stark, Lucinda Murray, Sebastian Lunke, Emily Fassi, Lauren Dreyer, Aimé Lumaka, Jullianne Diaz, Koenraad Devriendt, Lisa Worgan, Hanyin Cheng, Pankaj B. Agrawal, Laurence Faivre, H. T. Marc Timmers, Julie Vogt, Elizabeth E. Palmer, Kai Wang, Nora Alexander, Michael F. Buckley, Tony Roscioli, Chunhua Weng, Gabriela Soares, Simona Capponi, Antonie D. Kline, Jorge Oliveira, Amali Mallawaarachchi, Ana R. Gonçalves, Gareth Baynam, Eyby Leon, Marcia C. Willing, Shehla Mohammed, Sarah A. Sandaradura, Elaine Marchi, Katelyn Payne, Amber Begtrup, Piatek G. Stefan, Lesley C. Adès, Mengge Zhao, Emma Wakeling, Jean-Baptiste Rivière, Sébastien Moutton, Quan Li, Maria J. Guillen Sacoto, Jeff L. Waugh, Jennifer E. Posey, Robert Kleyner, Alan F. Rope, Prosper Lukusa, James R. Lupski, Laurence E. Walsh, Joris Vermeesch, Gholson J. Lyon, and Sonja A. de Munnik
Subjects: Genetics, TAF1, Missense mutation, Biology, Pathogenicity, Phenotype, Genetics (clinical)
Published: 2020
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41. De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

Author: Lilian Bomme Ousager, Anne Gregor, Bruno Dallapiccola, Sébastien Moutton, Marwan Shinawi, Heather C Mefford, Eduardo Calpena, Satoko Kumada, Joseph D. Symonds, Candace T. Myers, Antonio Novelli, Melissa Lees, Bertrand Isidor, Tobias B. Haack, Augusta M. A. Lachmeijer, Francisco Martínez, Anita Rauch, André Reis, Carmen Orellana, Pascal Joset, Rebecca Buchert, Laurence Faivre, Naomichi Matsumoto, Frances Elmslie, Ajoy Sarkar, Katharina Steindl, Mónica Roselló, Ingrid E. Scheffer, Lynette G. Sadleir, Victoria Harrison, Agatino Battaglia, Alex Henderson, Sally Ann Lynch, Felix Distelmaier, Ange Line Bruel, Paranchai Boonsawat, Noriko Miyake, Heinrich Sticht, David Hunt, Carey McDougall, Addie I. Nesbitt, Silvia Azzarello-Burri, Avni Santani, Reza Asadollahi, Benjamin Cogné, Elaine H. Zackai, Ken Saida, Christiane Zweier, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], St. George's Hospital, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Newcastle Upon Tyne Hospitals NHS Trust, Temple Street Children's University Hospital [Dublin], Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Children’s Hospital of Philadelphia (CHOP ), Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Departments of Medicine and Paediatrics (Austin Health and Royal Children’s Hospital), University of Melbourne-Austin Health, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, and Bioinformatik, Institut für Biochemie
Subjects: 0301 basic medicine, Male, Microcephaly, FBXO11, intellectual disability, neurodevelopmental disorder, Proteasome Endopeptidase Complex, Protein-Arginine N-Methyltransferases, Protein family, Ubiquitin-Protein Ligases, FBXO11, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Report, Intellectual Disability, Exome Sequencing, medicine, Genetics, Missense mutation, Humans, Genetics(clinical), Exome, Child, Genetics (clinical), Loss function, Exome sequencing, Genetic Association Studies, F-Box Proteins, Ubiquitination, Genetic Variation, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Female, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract: International audience; Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
Published: 2018
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42. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

Author: Cyril Goizet, Christophe Philippe, P. Charles, M. Assoum, N. Houcinat, Elisabeth Sarrazin, Martin Chevarin, Sébastien Moutton, Antonio Vitobello, A. Charollais, Ange-Line Bruel, Yannis Duffourd, Christel Thauvin-Robinet, F. Tran-Mau-Them, A. Faudet, Anne-Marie Guerrot, Laurence Faivre, Delphine Héron, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Proband, Adult, Male, Adolescent, marfanoid, synaptopathy, Biology, Frameshift mutation, Marfan Syndrome, whole exome sequencing, Cohort Studies, 03 medical and health sciences, Young Adult, Intellectual disability, Genetics, medicine, Humans, RNA, Messenger, Child, Gene, PSD-95, Genetics (clinical), Exome sequencing, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genome, Human, Marfanoid, Middle Aged, medicine.disease, DLG4, 030104 developmental biology, intellectual disability, Mutation, Female, Haploinsufficiency, Disks Large Homolog 4 Protein
Abstract: IF 3.512; International audience; Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.
Published: 2018
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43. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Author: Paola Francesca Ajmone, Maria Luisa Poch-Olive, Jens Erik Klint Nielsen, Christiane Zweier, Giovanni Sorge, Marzia Pollazzon, Bert Callewaert, Jeroen Breckpot, Olivera Djuric, Chiara Baldo, Rikke S. Møller, Isabella Mammi, Livia Garavelli, Gioacchino Scarano, Baris Malbora, Alessandro Iodice, Lucio Giordano, Marina Grasso, Alessandro Pellicciari, Marcella Zollino, Daniele De Brasi, Aurélien Trimouille, Ebtesam M. Abdalla, Samantha A. Schrier Vergano, Ina Schanze, Sébastien Moutton, Anna Kutkowska-Kazmierczak, Agata Fiumara, Andrea Conidi, Emilia Ricci, Duccio Maria Cordelli, Roberta Epifanio, Allan Bayat, Federico Bonvicini, Magdalena Badura-Stronka, Lorenzo Iughetti, Tina Duelund Hjortshøj, Anita Rauch, Vladimir Kuburovic, Giulia Montorsi, Elvis rci Te Valera, Debora Formisano, Stefano Giuseppe Caraffi, Krzysztof Szczaluba, Daniela Santodirocco, Sabine Grønborg, Francesca Faravelli, Maria Antonietta Pisanti, Didier Lacombe, Gijs W. E. Santen, Margherita Silengo, Ivan Ivanovski, Luis G. Tone, Goran Cuturilo, Francesca Mari, Guido Cocchi, Margaret P. Adam, Simonetta Rosato, Chiara Pantaleoni, Patrizia Accorsi, Nicoletta Zanotta, Ewa Obersztyn, Maddalena Baldi, Angelo Selicorni, Alessandra Renieri, Annick Toutain, Mary Beth Dinulos, Petra Muschke, Luigina Spaccini, Luigi Tarani, Igor Prpić, Francesca Rivieri, Koenraad Devriendt, Stefania Bigoni, Robert Smigiel, Anna Luchetti, Federico Raviglione, Martin Zenker, Caterina Lo Rizzo, Salvatore Savasta, Cell biology, and Ivan Ivanovski, Olivera Djuric, Stefano Giuseppe Caraffi, Daniela Santodirocco, Marzia Pollazzon, Simonetta Rosato, Duccio Maria Cordelli, Ebtesam Abballa, Patrizia Accorsi, Margaret P. Adam, Paola Francesca Ajmone, Magdalena Badura-Stronka, Chiara Baldo, Maddalena Baldi, Allan Bayat, Stefania Bigoni, Federico Bonvicini, Jeroen Breckpot, Bert Callewaert, Guido Cocchi, Goran Cuturilo, Daniele De Brasi, Koenraad Devriendt Mary Beth Dinulos, Tina Duelund Hjortshøj, Roberta Epifanio, Francesca Faravelli, Agata Fiumara, Debora Formisano, Lucio Giordano, Marina Grasso, Sabine Grønborg, Alessandro Iodice, Lorenzo Iughetti, Vladimir Kuburovic, Anna Kutkowska-Kazmierczak, Didier Lacombe, Caterina Lo Rizzo, Anna Luchetti, Baris Malbora, Isabella Mammi, Francesca Mari, Giulia Montorsi, Sebastien Moutton, Rikke S. Møller, Petra Muschke, Jens Erik Klint Nielsen, Ewa Obersztyn, Chiara Pantaleoni, Alessandro Pellicciari, Maria Antonietta Pisanti, Igor Prpic, Maria Luisa Poch-Olive, Federico Raviglione, Alessandra Renieri, Emilia Ricci, Francesca Rivieri, Gijs W. Santen, Salvatore Savasta, Gioacchino Scarano, Ina Schanze, Angelo Selicorni, Margherita Silengo, Robert Smigiel, Luigina Spaccini, Giovanni Sorge, Krzysztof Szczaluba, Luigi Tarani, Luis Gonzaga Tone, Annick Toutain, Aurelien Trimouille, Elvis Terci Valera, Samantha Schrier Vergano, Nicoletta Zanotta, Martin Zenker, Andrea Conidi, Marcella Zollino, Anita Rauch, Christiane Zweier, Livia Garavelli
Subjects: 0301 basic medicine, Male, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, Microcephaly/diagnosis, Settore MED/03 - GENETICA MEDICA, Bioinformatics, Hirschsprung, intellectual disability, management, Mowat–Wilson syndrome, ZEB2, Hirschsprung Disease/diagnosis, BOX 1B GENE, Abnormalities, Multiple/genetics, Genotype, Intellectual disability, Medicine and Health Sciences, Missense mutation, Mowat-Wilson syndrome, Family history, Child, Genetics (clinical), BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, Intellectual Disability/diagnosis, Phenotype, ZEB2 gene. Mowat-Wilson syndrome, intellectual disability, 3. Good health, SIBLINGS, Child, Preschool, Microcephaly, Female, Adult, Hirschsprung, intellectual disability, management, Mowat–Wilson syndrome, ZEB2, Adolescent, 03 medical and health sciences, Genetic variation, medicine, Humans, Abnormalities, Multiple, Hirschsprung Disease, RECURRENCE, ZFHX1B MUTATIONS, Genetic Association Studies, Genetic association, Zinc Finger E-box Binding Homeobox 2, SPECTRUM, SMAD-INTERACTING PROTEIN-1, business.industry, CLINICAL-FEATURES, ZEB2 gene. Mowat-Wilson syndrome, Biology and Life Sciences, Facies, Infant, HIRSCHSPRUNG-DISEASE, medicine.disease, Zinc Finger E-box Binding Homeobox 2/genetics, DELINEATION, Genetic Association Studies/methods, 030104 developmental biology, Mutation, business, MENTAL-RETARDATION
Abstract: PurposeMowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221. ispartof: Genetics in Medicine vol:20 issue:9 pages:965-975 ispartof: location:United States status: published
Published: 2018
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44. Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant

Author: Chloé Angelini, Didier Lacombe, Julien Van Gils, Pierre-Simon Jouk, Cyril Goizet, Marie Vincent, Florence Riant, Sébastien Moutton, Patrice Menegon, Guilhem Solé, Aurélien Trimouille, Elisabeth Tournier-Lasserve, Antoine Bigourdan, U 1211 Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (MRGM), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale du CHU de Bordeaux, Département de Neuro-Radiologie [Bordeaux] (DNR - Bordeaux), CHU Bordeaux [Bordeaux], Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique moléculaire neurovasculaire, groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal, 75010 Paris, France., Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], and Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, Adult, Male, Ataxia, Genetic counseling, Mutation, Missense, Penetrance, 030105 genetics & heredity, Bioinformatics, CACNA1A, 03 medical and health sciences, Epilepsy, Genetics, medicine, Spinocerebellar ataxia type 6, Humans, Child, Genetics (clinical), Familial hemiplegic migraine, Aged, Spinocerebellar Degenerations, Episodic ataxia, Incomplete penetrance, Genetic counselling, business.industry, Genetic heterogeneity, Epileptic encephalopathy, General Medicine, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, Calcium Channels, medicine.symptom, business
Abstract: IF 2.004 (2017); International audience; The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.
Published: 2018
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45. In utero seizures revealing dentato-olivary dysplasia caused by SCN2A mutation

Author: Dominique Carles, Christophe Pécheux, Gwenaëlle André, Fanny Sauvestre, Bernard Broussin, Caroline Lacoste, Laurent Villard, Fanny Pelluard, Sébastien Moutton, Nada Houcinat, Annie Laquerrière, Catherine Badens, Florent Marguet, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
Subjects: Pathology, medicine.medical_specialty, Histology, Encephalopathy, medicine.disease_cause, Bioinformatics, Pathology and Forensic Medicine, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic linkage, Physiology (medical), medicine, Gene, ComputingMilieux_MISCELLANEOUS, Mutation, 030219 obstetrics & reproductive medicine, business.industry, medicine.disease, 3. Good health, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dysplasia, In utero, Autism, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Most early-onset epileptic encephalopathies (EOEE) are caused by genetic defects. In the past, mutations, especially in genes encoding sodium channels, have been identified using linkage studies, array-CGH and more recently next-generation sequencing (NGS) [1]. Mutations in SCN2A gene have been identified in a wide variety of early-onset epileptic syndromes including benign familial neonatal infantile seizures (BFNIS) [2] and more severe forms leading to encephalopathy such as Ohtahara or West syndromes [3], epilepsy of infancy with migrating focal seizures (EIMFS) [4] and autism spectrum disorders [5]. In 2013, mutations in SCN2A gene were reported with dentato-olivary dysplasia (DOD) in a single family [6] but the link between DOD and severe EOEE needs to be confirmed [6]. This article is protected by copyright. All rights reserved.
Published: 2017
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46. New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay

Author: Rodrigue Rossignol, Isabelle Coupry, Michel Koenig, Magalie Barth, Cyril Goizet, Nadège Bellance, Dominique Bonneau, Agnès Guichet, Diana Rodriguez, Christelle M. Durand, Nada Houcinat, Julie Bouron, Sébastien Moutton, Julie Lavie, Sandra Chantot-Bastaraud, Julie Pilliod, Alexandra Durr, Karine Nguyen, Alexis Brice, Didier Hannequin, Giovanni Benard, Mathieu Anheim, Perrine Charles, Christel Thauvin-Robinet, Alexandra Afenjar, Elise Maurat, Guillaume Fromager, Patrick Berquin, Didier Lacombe, Caroline Rooryck, Dan Milea, Sylvie Forlani, Philippe Convers, Elisabeth Maillart, Christophe Verny, Stéphanie Valence, Julien Van-Gils, Fanny Mochel, Christophe Hubert, Giovanni Stevanin, Lucie Guyant-Maréchal, Lydie Burglen, and Gaetan Lesca
Subjects: Genetics, Mutation, Ataxia, Mitochondrion, Biology, medicine.disease_cause, medicine.disease, 3. Good health, Neurology, medicine, Spinocerebellar ataxia, Biomarker (medicine), Missense mutation, Neurology (clinical), medicine.symptom, Gene, Exome sequencing
Abstract: Objective Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment. Methods A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene. Results We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested. Interpretation Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria. Ann Neurol 2015;78:871–886
Published: 2015
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47. Fetal phenotypes in otopalatodigital spectrum disorders

Author: Philippe Loget, Didier Lacombe, Marie-Pierre Cordier, Sébastien Moutton, Cyril Goizet, C. Abel, Cédric Hubert, Sophie Patrier, Julie Pilliod, G. Viot, Benoit Arveiler, Bettina Bessières, Alice Goldenberg, Julie Deforges, Isabelle Coupry, Caroline Rooryck, G. Sole, Anne-Lise Delezoide, Sophie Blesson, Patricia Fergelot, Elodie Guerineau, Alain Verloes, Judith Melki, F. Le Breton, S. Deves, Sophie Collardeau-Frachon, Sylvie Odent, and Sophie Naudion
Subjects: 0301 basic medicine, Genetics, Mutation, Mutation rate, Omphalocele, Craniofacial abnormality, Genetic counseling, 030105 genetics & heredity, Biology, medicine.disease_cause, Bioinformatics, medicine.disease, 3. Good health, 03 medical and health sciences, Dysplasia, medicine, FLNA, Obstructive uropathy, Genetics (clinical)
Abstract: Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.
Published: 2015
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48. Homozygous 16p13.11 duplication associated with mild intellectual disability and urinary tract malformations in two siblings born from consanguineous parents

Author: Benoit Arveiler, Jérôme Toutain, Dorothée Cailley, Sébastien Moutton, Didier Lacombe, Caroline Rooryck, Nada Houcinat, B. Llanas, and C. Combe
Subjects: Adult, Male, Parents, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Urinary system, Consanguinity, Intellectual Disability, Chromosome Duplication, Gene duplication, Intellectual disability, Genetics, Humans, Medicine, Copy-number variation, Urinary Tract, Genetics (clinical), Comparative Genomic Hybridization, Kidney, business.industry, Siblings, Homozygote, Infant, Newborn, Infant, Chronic renal disease, medicine.disease, Phenotype, Pedigree, medicine.anatomical_structure, Female, business, Chromosomes, Human, Pair 16, Cohort study
Abstract: The use of array-comparative genomic hybridization (array-CGH) in routine clinical work has allowed the identification of many new copy number variations (CNV). The 16p13.11 duplication has been implicated in various congenital anomalies and neurodevelopmental disorders, but it has also been identified in healthy individuals. We report a clinical observation of two brothers from related parents each carrying a homozygous 16p13.11 duplication. The propositus had mild intellectual disability and posterior urethral valves with chronic renal disease. His brother was considered a healthy child with only learning disabilities and poor academic performances. However, a routine medical examination at 25-years-old revealed a mild chronic renal disease and ureteropelvic junction obstruction. Furthermore, the father presented with a unilateral renal agenesis, thus it seemed that a “congenital anomalies of kidney and urinary tract” (CAKUT) phenotype segregated in this family. This may be related to the duplication, but we cannot exclude the involvement of additional genetic or non-genetic factors in the urological phenotype. Several cohort studies showed association between this chromosomal imbalance and different clinical manifestations, but rarely with CAKUT. The duplication reported here was similar to the larger one of 3.4 Mb previously described versus the more common of 1.6 Mb. It encompassed at least 11 known genes, including the five ohnologs previously identified. Our observation, in addition to expanding the clinical spectrum of the duplication provides further support to understanding the underlying pathogenic mechanism. © 2015 Wiley Periodicals, Inc.
Published: 2015
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49. Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy

Author: Michel Vanasse, Amy Pizzino, Adeline Vanderver, Félixe Pelletier, Renee Myriam Boucher, Luan T. Tran, Geneviève Bernard, Nancy Braverman, Federico Roncarolo, Stephanie Keller, Myriam Srour, Cyril Goizet, Elsa Rossignol, Bradley Osterman, Marcelo Andrés Kauffman, Amytice Mirchi, Sébastien Moutton, Daniela Pohl, Sunita Venkateswaran, Michael Shevell, Davide Tonduti, Guillaume Sébire, Chantal Poulin, Annette Majnemer, John J. Mitchell, Marie Emmanuelle Dilenge, and Raphael Schiffmann
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, medicine.medical_treatment, 030105 genetics & heredity, Severity of Illness Index, Leukoencephalopathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Wheelchair, Quality of life (healthcare), Developmental Neuroscience, Leukoencephalopathies, Medicine, Humans, Prospective cohort study, Child, Dystonia, Sialorrhea, business.industry, Infant, medicine.disease, Gastrostomy, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, Quality of Life, Female, Neurology (clinical), business, Psychosocial, 030217 neurology & neurosurgery
Abstract: Background We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. Methods Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. Results Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. Conclusions Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.
Published: 2017

50. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Author: Montserrat Rodríguez-Ballesteros, Laurence Faivre, Pierre-Simon Jouk, Christine Francannet, Damien Sanlaville, Sophie Naudion, Hélène Dollfus, Nicole Philip, Pierre Sarda, Marine Legendre, X. Piguel, Alice Masurel-Paulet, Marie-Ange Delrue, Frédéric Bilan, Aurélia Jacquette, Dominique Bonneau, Catherine Vincent-Delorme, Valérie Layet, Michèle Mathieu-Dramard, Delphine Héron, Sébastien Moutton, Alice Goldenberg, Sophie Julia, Sophie Blesson, Sylvie Odent, Philippe Parent, Chloé Quélin, Estelle Colin, Mélanie Fradin, Anne-Marie Guerrot, David Geneviève, Lucile Pinson, Renaud Touraine, Sabine Sigaudy, Stéphanie Ragot, Didier Lacombe, Massimiliano Rossi, Salima El Chehadeh, Tiffany Busa, Annick Toutain, Stanislas Lyonnet, Véronique Abadie, Bruno Leheup, Dominique Martin-Coignard, Tania Attié-Bitach, Brigitte Gilbert-Dussardier, Sandra Mercier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Endocrinologie [CHU Poitiers], Service Génétique Médicale [CHU Poitiers], French Ministry of Health ID-RCB: 2010-A00700-39, Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Médecine Aérospatiale du Service de Santé des Armées ( IMASSA ), Service de Santé des Armées, Université d'Angers ( UA ) -CHU Angers, Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Bretonneau-CHRU Tours, Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique médicale et cytogénétique [Le Mans], CH Le Mans, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, CHU - HÔTEL-DIEU Clermont-Ferrand, CHU Bordeaux [Bordeaux], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Cardiologie, Pôle DUNE, CHU de Poitiers, Centre d' investigation clinique-plurithématique du CHU de Poitiers, Génétique Médicale, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, université de Bourgogne, GAD, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Central Nervous System, Male, update, Choanal atresia, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Gastroenterology, spectrum, Cohort Studies, CHARGE syndrome, Genotype, Medicine, Child, Genetics (clinical), Coloboma, Genetic disorder, Cranial Nerves, Hypoplasia, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, Child, Preschool, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Anosmia, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, otorhinolaryngologic diseases, Humans, Abnormalities, Multiple, Genetic Testing, Alleles, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, association, DNA Helicases, Infant, medicine.disease, mutations, diagnostic-criteria, 030104 developmental biology, Amino Acid Substitution, Atresia, chd7 gene, proposal, CHARGE Syndrome, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
Published: 2017
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