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1. 10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France

Author: Claude Messiaen, Caroline Racine, Ahlem Khatim, Louis Soussand, Sylvie Odent, Didier Lacombe, Sylvie Manouvrier, Patrick Edery, Sabine Sigaudy, David Geneviève, Christel Thauvin-Robinet, Laurent Pasquier, Florence Petit, Massimiliano Rossi, Marjolaine Willems, Tania Attié-Bitach, Pierre-Henry Roux-Levy, Laurent Demougeot, Lilia Ben Slama, Paul Landais, the AnDDI-Rares network, Anne-Sophie Jannot, Christine Binquet, Arnaud Sandrin, Alain Verloes, and Laurence Faivre
Subjects: Rare disease, Developmental disorders, Data warehouse, Epidemiology, Medicine
Abstract: Abstract Background In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation. Methods Since 2007, clinicians and researchers have reported the “minimum dataset (MDS)” for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses. Results Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient’s home was 25.1 km (IQR = 6.3 km-64.2 km). Conclusions CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
Published: 2021
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2. Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders

Author: Michael Smith, Elizabeth Alexander, Ruta Marcinkute, Dorica Dan, Myfanwy Rawson, Siddharth Banka, Jason Gavin, Hany Mina, Con Hennessy, Florence Riccardi, Francesca Clementina Radio, Marketa Havlovicova, Matteo Cassina, Adela Chirita Emandi, Melanie Fradin, Lianne Gompertz, Ann Nordgren, Rasa Traberg, Massimiliano Rossi, Aurelién Trimouille, Rasika Sowmyalakshmi, Bruno Dallapiccola, Alessandra Renieri, Laurence Faivre, Bronwyn Kerr, Alain Verloes, Jill Clayton-Smith, Sofia Douzgou, and on behalf of ERN ITHACA
Subjects: European reference network, Developmental disorders, Telemedicine, Rare disease, Medicine
Abstract: Abstract Background The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. Results ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. Conclusions We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.
Published: 2020
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3. Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder

Author: Julie Masson, Caroline Demily, Nicolas Chatron, Audrey Labalme, Pierre-Antoine Rollat-Farnier, Caroline Schluth-Bolard, Brigitte Gilbert-Dussardier, Fabienne Giuliano, Renaud Touraine, Sylvie Tordjman, Alain Verloes, Giuseppe Testa, Damien Sanlaville, Patrick Edery, Gaetan Lesca, and Massimiliano Rossi
Subjects: Autism Spectrum Disorder, Williams Beuren syndrome, 7q11.23 microdeletion, GTF2I, Whole exome sequencing, Medicine
Abstract: Abstract Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.
Published: 2019
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4. Autistic disorder in patients with Williams-Beuren syndrome: a reconsideration of the Williams-Beuren syndrome phenotype.

Author: Sylvie Tordjman, George M Anderson, Michel Botbol, Annick Toutain, Pierre Sarda, Michèle Carlier, Pascale Saugier-Veber, Clarisse Baumann, David Cohen, Céline Lagneaux, Anne-Claude Tabet, and Alain Verloes
Subjects: Medicine, Science
Abstract: BackgroundWilliams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder.MethodologyThe study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH.FindingsFISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time.ConclusionsThe results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism.
Published: 2012
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5. NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study

Author: Cecilia Altuzarra, Altynshash Jaxybayeva, Marta Gomez Garcia de la Banda, Bakhytkul Myrzaliyeva, Jon Andoni Urtizberea, Jean-Michel Vallat, Raluca Anca Tudorache, Meriem Tazir, Andoni Echaniz-Laguna, Alain Verloes, Susana Quijano-Roy, and Bruno Francou
Subjects: medicine.medical_specialty, Neurology, medicine.diagnostic_test, business.industry, Retrospective cohort study, Consanguinity, medicine.disease, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Congenital insensitivity to pain with anhidrosis, Internal medicine, Biopsy, Genetics, medicine, Family history, Anhidrosis, medicine.symptom, business, Genetics (clinical), Sensory nerve
Abstract: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4–20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3–6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations.
Published: 2021
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6. Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma

Author: Julie Pernin-Grandjean, Sébastien Marchasson, Marion Aubert-Mucca, Nicolas Chassaing, Sabine Sigaudy, Christophe Habib, Pierre Bitoun, Olivier Roche, Danièle Denis, Julie Plaisancié, Isabelle Meunier, Josseline Kaplan, V. Gaston, Alain Verloes, Patrick Calvas, and Damien Haye
Subjects: Adult, Adolescent, Receptors, Retinoic Acid, Ocular Coloboma, Bioinformatics, Microphthalmia, Article, TFAP2A, Gene Frequency, Genetics, medicine, Humans, Inheritance Patterns, Child, Eye Proteins, Gene, Genetics (clinical), Aged, Coloboma, Genetic heterogeneity, business.industry, Intracellular Signaling Peptides and Proteins, Middle Aged, medicine.disease, Frizzled Receptors, eye diseases, Transcription Factor AP-2, Child, Preschool, Cohort, sense organs, business, Retinol-Binding Proteins, Plasma
Abstract: Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.
Published: 2020
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7. Overlapping phenotypes between <scp>SHORT</scp> and Noonan syndromes in patients with <scp> PTPN11 </scp> pathogenic variants

Author: Charles Marques, Yline Capri, Anne Guimier, A. Micheil Innes, Jeanne Amiel, Martine Auclair, Julien Thevenon, David A. Dyment, Gilles Morin, Christel Thauvin-Robinet, Corinne Vigouroux, Emmanuelle Ranza, Michèle Mathieu-Dramard, Alain Verloes, and Laurence Faivre
Subjects: Male, musculoskeletal diseases, 0301 basic medicine, MAPK/ERK pathway, congenital, hereditary, and neonatal diseases and abnormalities, MAP Kinase Signaling System, Protein Tyrosine Phosphatase, Non-Receptor Type 11, 030105 genetics & heredity, Biology, Gene product, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Metabolic Diseases, Genetics, medicine, Humans, Missense mutation, skin and connective tissue diseases, Protein kinase B, Growth Disorders, Genetics (clinical), Genetic heterogeneity, Noonan Syndrome, Genetic Variation, medicine.disease, PTPN11, Nephrocalcinosis, Phenotype, 030104 developmental biology, SHORT syndrome, Hypercalcemia, Noonan syndrome, Female, Mitogen-Activated Protein Kinases, Signal Transduction
Abstract: Overlapping syndromes such as Noonan, Cardio-Facio-Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease-causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease-causing gene being PIK3R1. Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling.
Published: 2020
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8. Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

Author: Philippine Garret, Sana Mahmoudi, Blandine Dozières-Puyravel, Frédéric Ebstein, Geoffroy Delplancq, Karun K. Singh, Elke Krüger, Yannis Duffourd, Laurence Faivre, Jean-Marc Costa, Barbara A. Zieba, Antonio Vitobello, Detlef Trost, Aïcha Boughalem, Stéphane Auvin, Sandro Klafack, Christel Thauvin-Robinet, Alain Verloes, and Laurence Duplomb
Subjects: Male, 0301 basic medicine, Heterozygote, Candidate gene, alpha7 Nicotinic Acetylcholine Receptor, Mutation, Missense, Chromosome Disorders, 030105 genetics & heredity, Mice, 03 medical and health sciences, Epilepsy, Seizures, Intellectual Disability, Exome Sequencing, Genetics, medicine, Animals, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Exome sequencing, Chromosomes, Human, Pair 15, Deubiquitinating Enzymes, business.industry, Homozygote, Proteasome complex, medicine.disease, Penetrance, Hypotonia, Phenotype, 030104 developmental biology, Female, Chromosome Deletion, medicine.symptom, business
Abstract: Heterozygous microdeletions of chromosome 15q13.3 (MIM: 612001) show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Rare patients carrying homozygous deletions show more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth. For years, CHRNA7 (MIM: 118511), was considered the candidate gene that could account for this syndrome. However, recent studies in mouse models have shown that OTUD7A/CEZANNE2 (MIM: 612024), which encodes for an ovarian tumor (OTU) deubiquitinase, should be considered the critical gene responsible for brain dysfunction. In this study, a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy was referred to our genetics center. Trio exome sequencing (tES) analysis identified a homozygous OTUD7A missense variant (NM_130901.2:c.697C>T), predicted to alter an ultraconserved amino acid, p.(Leu233Phe), lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient-derived fibroblasts and in OTUD7A knockout HAP1 cell line. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early-onset epileptic encephalopathy and proteasome dysfunction.
Published: 2020
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9. Phenotypes and genotypes in non‐consanguineous and consanguineous primary microcephaly: High incidence of epilepsy

Author: Bettina Blaumeiser, Alec Aeby, Marc Abramowicz, Isabelle Pirson, Cindy Badoer, Helene Verhelst, Kathelijn Keymolen, Berten Ceulemans, Hilde Van Esch, Stéphanie Moortgat, Anne Destree, Patrick Van Bogaert, Sarah Duerinckx, Yusuf Tunca, Valérie Jacquemin, Olivier Vanakker, Nicolas Deconinck, Sarah Weckhuysen, Camille Perazzolo, Marije E.C. Meuwissen, Anna Jansen, Sandrine Passemard, Damien Lederer, Winnie Courtens, Rudy Van Coster, Koenraad Devriendt, Tayeb Sekhara, Nathalie Van der Aa, Isabelle Maystadt, Bart Loeys, Julie Soblet, François-Guillaume Debray, Marie-Cécile Nassogne, Geert Mortier, Julie Désir, Alain Verloes, Catheline Vilain, Jenny Van Den Ende, UCL - (SLuc) Service de neurologie pédiatrique, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de référence en lésions congénitales de la moëlle épinière, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, Neuroprotection & Neuromodulation, Pediatrics, Clinical sciences, and Medical Genetics
Subjects: Male, Pediatrics, Candidate gene, Microcephaly, ASPM MUTATIONS, PROTEIN, Cell Cycle Proteins, QH426-470, FAMILIES, Consanguinity, Epilepsy, Gene Frequency, Medicine and Health Sciences, SEQUENCE VARIANTS, HETEROGENEITY, Child, Genetics (clinical), SNPS, Genetics & Heredity, Mendeliome, Seizure types, Incidence, primary microcephaly, Phenotype, Cohort, Original Article, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Genotype, rare disease, Nerve Tissue Proteins, ASPM, Genetic Heterogeneity, consanguinity, Genetics, medicine, Humans, PRENATAL-DIAGNOSIS, Molecular Biology, WDR62, Science & Technology, Genetic heterogeneity, business.industry, brain developmental disorders, Généralités, Original Articles, FRAMEWORK, medicine.disease, epilepsy, Human medicine, business
Abstract: Background: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Results: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Conclusion: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2021
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10. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author: Sylviane Marouillat, Marie-Laure Vuillaume, Thomas Smol, Rose-Anne Thépault, Lyse Ruaud, Sarah Grotto, Jamal Ghoumid, Nicolas Chatron, Annick Toutain, Marianne Till, Alain Verloes, Manon Dixneuf, Valérie Chune, Gaetan Lesca, Frédéric Laumonnier, Nathalie Couque, Bénédicte Gérard, Martine Raynaud, Judith Halewa, Dévina C. Ung, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), 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), Les Hôpitaux Universitaires de Strasbourg (HUS), 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), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ANR-20-CE17-0006,ASDecode,Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux(2020), Laumonnier, Frédéric, Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux - - ASDecode2020 - ANR-20-CE17-0006 - AAPG2020 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Male, [SDV]Life Sciences [q-bio], Mutation, Missense, autism spectrum disorder, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, functional analyses, PTCHD1 (patched domain containing 1) gene, 03 medical and health sciences, Mice, in vitro cellular models, subcellular localization, Genetics, medicine, Missense mutation, Animals, Humans, Gene, Genetics (clinical), Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Endoplasmic reticulum, 030305 genetics & heredity, Cell Membrane, Membrane Proteins, Subcellular localization, medicine.disease, In vitro, Transmembrane protein, Amino acid, [SDV] Life Sciences [q-bio], chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, missense variants, Research Article
Abstract: The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD., Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.
Published: 2021
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11. EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder

Author: Jessica Assoumani, Morgane Plutino, Caroline Benech, Nathalie Marle, Houda Karmous-Benailly, Elise Boudry Labis, Sylvia Redon, Lionel Van Maldergem, Hala Nasser, Nathalie Couque, Myriam Rachid, Anne-Claude Tabet, Bérénice Schell, Aafke Engwerda, Mélanie Rama, Odile Boute, Céline Dupont, Conny M. A. van Ravenswaaij-Arts, Patrick Callier, Lyse Ruaud, Jonathan I. Levy, Paul Kuentz, Alain Verloes, Laurence Faivre, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University Medical Center Groningen [Groningen] (UMCG), Centre Hospitalier Universitaire de Nice (CHU Nice), EFS, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Lille, Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de génétique médicale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]., Clinical Cognitive Neuropsychiatry Research Program (CCNP), PODEUR, Sophie, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)
Subjects: Male, Microcephaly, [SDV]Life Sciences [q-bio], 6q16, 1 microdeletion, Inheritance Patterns, EPHA7, Haploinsufficiency, Biology, speech and language development, Neurodevelopmental disorder, Exome Sequencing, Genetics, medicine, Ephrin, Humans, Genetic Predisposition to Disease, microcephaly, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, 6q16.1 microdeletion, Erythropoietin-producing hepatocellular (Eph) receptor, Receptor, EphA7, medicine.disease, Penetrance, Phenotype, neurodevelopmental disorder, Pedigree, [SDV] Life Sciences [q-bio], Neurodevelopmental Disorders, intellectual disability, Mutation, Chromosomes, Human, Pair 6, Female
Abstract: International audience; Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.
Published: 2021
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12. Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion

Author: Patrick Aubourg, Jean-Marie Cuisset, Philippe Latour, Kouider Beladgham, Jimmy Perrot, Lucie Guyant-Marechal, Bruno Francou, Laurent Kremer, Naziha Baaloul, Alain Verloes, and Andoni Echaniz-Laguna
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Weakness, Pes cavus, Adolescent, Encephalopathy, Consanguinity, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetics, medicine, Humans, Child, Genetics (clinical), Retrospective Studies, Giant axonal neuropathy, business.industry, Gigaxonin, Brain, medicine.disease, Cytoskeletal Proteins, 030104 developmental biology, medicine.anatomical_structure, Giant Axonal Neuropathy, Child, Preschool, Peripheral nervous system, Mutation, Female, medicine.symptom, business, Polyneuropathy, 030217 neurology & neurosurgery
Abstract: Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.
Published: 2019
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13. Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Author: Francesca Romana Lepri, Martin Zenker, Christina Lißewski, Alma Kuechler, Lisa M. Vincent, Elisabetta Flex, Elaine Suk-Ying Goh, Francesca Pantaleoni, Serena Cecchetti, Yline Capri, Kristin G. Monaghan, Giovanna Carpentieri, Mohammad Reza Ahmadian, Marion Strullu, Goran Cuturilo, Hélène Cavé, Cédric Vignal, Alain Verloes, Nuria C. Bramswig, Julia Meyer, Neda S. Kazemein Jasemi, Elliot Stieglitz, Denny Schanze, Oliver H.F. Krumbach, Karen Chong, Radovan Dvorsky, Soheila Rezaei Adariani, Stephanie Sacharow, Marco Tartaglia, Julia Brinkmann, Yoann Vial, Juliette Piard, and G. Kensah
Subjects: Male, 0301 basic medicine, MAPK/ERK pathway, Protein Conformation, Medizin, GTPase, 030105 genetics & heredity, MAPK cascade, Medical and Health Sciences, Noonan syndrome, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Exome sequencing, Pediatric, Genetics & Heredity, Genetics, Noonan Syndrome, Biological Sciences, Pedigree, Gain of Function Mutation, Female, Guanosine Triphosphate, RRAS2, Adult, Intellectual and Developmental Disabilities (IDD), Biology, 03 medical and health sciences, Downregulation and upregulation, Report, medicine, Humans, RASopathies, Gene, Genetic Association Studies, Monomeric GTP-Binding Proteins, Genetic heterogeneity, Infant, Newborn, Infant, Membrane Proteins, Newborn, medicine.disease, MAPK, Brain Disorders, HEK293 Cells, 030104 developmental biology, Congenital Structural Anomalies, RAS
Abstract: Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cellmorphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
Published: 2019
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14. Author response for 'EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder'

Author: Odile Boute, Lyse Ruaud, Aafke Engwerda, Anne-Claude Tabet, Lionel Van Maldergem, Patrick Callier, Bérénice Schell, Céline Dupont, Jessica Assoumani, Caroline Benech, Nathalie Marle, Nathalie Couque, Houda Karmous-Benailly, Jonathan Levy, Elise Boudry Labis, Mélanie Rama, Alain Verloes, Sylvia Redon, Myriam Rachid, Conny M. A. Ravenswaaij‐Arts, Laurence Faivre, Morgane Plutino, Paul Kuentz, and Hala Nasser
Subjects: Neurodevelopmental disorder, business.industry, medicine, EPHA7, medicine.disease, Haploinsufficiency, business, Neuroscience
Published: 2021
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15. Phenotypes and genotypes in outbred and inbred Primary microcephaly: high incidence of epilepsy

Author: Julie Désir, Catheline Vilain, Sarah Duerinckx, Isabelle Pirson, Olivier Vanakker, Tayeb Sekhara, Bart Loeys, Camille Perazzolo, Marije E.C. Meuwissen, Geert Mortier, Cindy Badoer, Kathelijn Keymolen, Bettina Blaumeiser, Gert Matthijs, Stéphanie Moortgat, Patrick Van Bogaert, Jenneke van den Ende, Yusuf Tunca, Hilde Van Esch, Marc Abramowicz, Julie Soblet, Koen Devriendt, Valérie Jacquemin, Anna Jansen, Sarah Weckhuysen, François-Guillaume Debray, Sandrine Passemard, Damien Lederer, Alain Verloes, Nathalie Van der Aa, Marie-Cécile Nassogne, Helene Verhelst, Alec Aeby, Anne Destree, Winnie Courtens, Isabelle Maystadt, Nicolas Deconinck, Berten Ceulemans, and Rudy Van Coster
Subjects: Oncology, Microcephaly, medicine.medical_specialty, Candidate gene, Genetic heterogeneity, business.industry, Seizure types, medicine.disease, ASPM, Epilepsy, Internal medicine, Cohort, Genotype, medicine, business
Abstract: Primary microcephaly (PM) is defined as a significant reduction in occipito-frontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n=169) of patients referred for PM, and could establish a molecular diagnosis in 38 patients. Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in outbred patients (9%). Our series includes 15 previously unreported families and 11 novel pathogenic variants, and we identify novel candidate genes including IGF2BP3, DNAH2, and TSR1. We confirm progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses and improve management of PM patients.
Published: 2021
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16. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

Author: Sylvain Vergnet, Jean Phillipe Azulay, Isabelle Meunier, Audrey Riquet, Olivier Patat, Anna Castrioto, Laurent Pasquier, Cyril Charlin, Lena Damaj, Cécile Acquaviva, Nicolas Lebouc, Bérénice Doray, Cecilia Marelli, Morgane Pointaux, Pierre Meyer, Perrine Charles, Danielle Cuntz-Shadfar, Caroline Tillikete, Frederic Villega, Cathy Lieutard-Haag, Michel Koenig, François Rivier, Idriss Bousquet, Ganaëlle Remerand, Ulrike Walther-Louvier, Clarisse Carra-Dalliere, Victoria Gonzales, Alexandre Eusebio, Brigitte Chabrol, Emilie Carme, Pierre Labauge, Adrian Degardin, Elise Brischoux-Boucher, Brice Laurens, Laurent Kremer, Giovanni Castelnovo, Mélanie Fradin, Mehdi Benkirane, Karine Nguyen, Jean-Marie Ravel, Vincent Laugel, Emilien Bernard, Claire Guissart, Cyril Goizet, Samira Sissaoui, Agathe Roubertie, Christine Francannet, Sylvie Odent, Yosra Halleb, Xavier Ayrignac, Shahram Attarian, Fabienne Ory Magne, David Geneviève, Joel Victor Fluss, Alain Verloes, Anne Rolland, Martial Mallaret, Lydia Abou Haidar, Nadia Bahi-Buisson, David Baux, Catherine Sarret, Nicolas Carrière, Christine Coubes, Mathilde Renaud, Claire Ewenczyk, Patrick Calvas, Solène Frismand, Leila Lazaro, Bertrand Isidor, Annabelle Chaussenot, Sophie Julia, Valerie Fraix, Elsa Kaphan, Tatiana Witjas, Frédérique Fluchère, Mathieu Anheim, Christine Tranchant, William Camu, Eric Thouvenot, Lise Larrieu, Eric Bieth, Ariane Choumert, Raoul Morales, Marinha Costa Moreira, Elizabeth Ollagnon, 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Clermont-Ferrand, 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), CHU Bordeaux [Bordeaux], Institut NeuroMyoGène (INMG), 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 Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, CHU Pontchaillou [Rennes], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospitals and Geneva University, Hôpital Robert Debré, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: medicine.medical_specialty, Ataxia, Cerebellar Ataxia, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Genomics, Biology, PEX10, Cohort Studies, Peroxins, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Translation reinitiation, 0303 health sciences, Molecular pathology, 030305 genetics & heredity, Phenotype, Human genetics, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, medicine.symptom, 030217 neurology & neurosurgery
Abstract: International audience; Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Published: 2021
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17. Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author: M Pettersson, Yannis Duffourd, Marco Tartaglia, Steven Laurie, Tobias B. Haack, Karolis Sablauskas, Andrea Ciolfi, Antonio Vitobello, Aurélien Trimouille, A Nordgren, E Lopez-Martin, A Hugon, K Vyshka, M Schwarz, M Janssen, S Li, Isabelle Nelson, S Prasanth, Christian Gilissen, Lelm Vissers, Rita Horvath, Simone Pizzi, G Casari, Leslie Matalonga, de, Boer, E, Caroline Rooryck, Siddharth Banka, Michele Pinelli, Mridul Johari, Christel Thauvin, Peter N. Robinson, M Posada, Wouter Steyaert, RJ Rodenburg, Marco Savarese, Jill Clayton-Smith, Ana Töpf, Annalaura Torella, A-S Denomme-Pichon, A Hammarsjo, Milan Macek, A Lindstrand, L Ryba, Elisa Benetti, Enzo Cohen, Birte Zurek, van, der, Velde, Jk, CW Ockeloen, D Henssen, Marketa Havlovicova, Daniel Danis, Francesca Clementina Radio, Bruno Dallapiccola, Mjh Coenen, Ida Paramonov, Tjitske Kleefstra, Laurence Faivre, Lisenka E.L.M. Vissers, I Cuesta, Alessandra Renieri, Alexander Hoischen, Alain Verloes, Adam Jackson, Nigro, and Sophia Peters
Subjects: 0303 health sciences, Pediatrics, medicine.medical_specialty, business.industry, 030305 genetics & heredity, medicine.disease, Human genetics, MT-TL1, 03 medical and health sciences, Epilepsy, Intellectual disability, Genetics, Spastic tetraparesis, Medicine, business, Genetics (clinical), Exome sequencing
Published: 2021
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18. Author response for '<scp>Smith‐Magenis</scp> syndrome ( <scp>SMS</scp> ): clinical and behavioral characteristics in a large retrospective cohort'

Author: David Geneviève, Jamal Ghoumid, Myriam Mikaty, Hélène Deleersnyder, Nicole Philip, Delphine Héron, Laurence Perrin, Lyse Ruaud, Faustine Ageorge, Adeline Jacquinet, Laurence Faivre, Sophie Chancenotte, Jennifer Gallard, Didier Lacombe, Nicolas Rive Le Gouard, Natacha Lehman, Patrick Edery, Christel Thauvin-Robinet, Sylvie Manouvrier-Hanu, Coralie Rastel, Sylvie Odent, and Alain Verloes
Subjects: Pediatrics, medicine.medical_specialty, business.industry, medicine, Retrospective cohort study, Smith–Magenis syndrome, medicine.disease, business
Published: 2020
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19. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Author: Katharina Steindl, Alain Verloes, Cornelia Kraus, Rachel Fisher, Katrin Õunap, Amber Begtrup, Steffen Syrbe, Theresa Brunet, Antonio Vitobello, Laurence Faivre, Reza Asadollahi, Jessica Becker, Maja Hempel, Dave A Dyment, Christiane Zweier, John H McDermott, Bernt Popp, Elaine Suk-Ying Goh, Lynette G. Sadleir, Anaïs Begemann, Siddharth Banka, Gwenaël Le Guyader, Elisabeth Schuler, Anne-Sophie Denommé-Pichon, Kathleen Brown, Gaetan Lesca, Frédéric Tran Mau-Them, Lucia Ribeiro Machado Haertel, Maryline Carneiro, Amelie Theresa Van der Ven, Markus Zweier, Hartmut Engels, Heinrich Sticht, Theresia Herget, Jessika Johannsen, Bader Alhaddad, Nadine N. Hauer, Robert C. Day, Tiia Reimand, M. J. Hajianpour, Manuel Schiff, Kirsty McWalter, Margarita Saenz, Tatjana Bierhals, Pierre Meyer, Ange-Line Bruel, Martina Russo, Korbinian M. Riedhammer, Kirsten Cremer, Anita Rauch, Marjolaine Willems, 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Robert Debré
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, WAVEregulatory complex (WRC), 030105 genetics & heredity, Biology, Article, Intellectual disability, Epilepsy, CYFIP2, WAVE-regulatory complex (WRC), WASF, 03 medical and health sciences, Neurodevelopmental disorder, Seizures, medicine, Missense mutation, Humans, Genetics(clinical), Gene, Genetics (clinical), Actin, Adaptor Proteins, Signal Transducing, Genetics, medicine.disease, Actin cytoskeleton, Phenotype, Hypotonia, Actins, 3. Good health, ddc, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neurodevelopmental Disorders, intellectual disability, epilepsy, medicine.symptom
Abstract: International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Published: 2020
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20. Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort

Author: Jamal Ghoumid, Patrick Edery, Christel Thauvin-Robinet, Sophie Chancenotte, Nicole Philip, Alain Verloes, Myriam Mikaty, Didier Lacombe, Coralie Rastel, Lyse Ruaud, David Geneviève, Natacha Lehman, Laurence Faivre, Laurence Perrin, Nicolas Rive Le Gouard, Hélène Deleersnyder, Adeline Jacquinet, Faustine Ageorges, Delphine Héron, Jennifer Gallard, Sylvie Odent, Sylvie Manouvrier-Hanu, 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), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (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), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Parents, Pediatrics, Developmental Disabilities, Smith-Magenis, 030105 genetics & heredity, Overweight, Epilepsy, Neurodevelopmental disorder, Prenatal Diagnosis, Child, clinical characteristics, Genetics (clinical), Growth Disorders, Tetralogy of Fallot, Sleep disorder, Smith–Magenis syndrome, 3. Good health, Phenotype, Child, Preschool, Education, Special, Family Relations, medicine.symptom, Chromosome Deletion, Sleep Wake Disorders, medicine.medical_specialty, Adolescent, Scoliosis, Child Behavior Disorders, obstipation, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Retrospective Studies, business.industry, Retrospective cohort study, Patient Acceptance of Health Care, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, social impact, 17p11.2, Smith-Magenis Syndrome, business, Chromosomes, Human, Pair 17
Abstract: International audience; Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
Published: 2020
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21. Author response for 'Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature'

Author: Laurence Faivre, Thibaud Jouan, Benjamin Cogné, Cornelia Kraus, V. Carmignac, Francis Ramond, Christiane Zweier, Emilie Tisserant, Mathilde Nizon, André Reis, Valérie Benoit, Daphné Lehalle, Antonio Vitobello, Bruno Delobel, Renaud Touraine, Thomas Smol, Arthur Sorlin, Yannis Duffourd, Sophie Naudion, Christel Thauvin-Robinet, T Bienvenu, Julien Thevenon, Caroline Thuillier, Patrick Callier, Stéphanie Moortgat, Frédéric Tran Mau-Them, Jamal Ghoumid, Christophe Philippe, Cécile Zordan, Sophie Nambot, and Alain Verloes
Subjects: business.industry, Female Phenotype, Immunology, Medicine, Disease, business
Published: 2020
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22. The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered

Author: Christine Fauth, Denny Schanze, Alper Gezdirici, Francis Ramond, Francesca Pantaleoni, Christina Lissewski, Violeta Iotova, Alain Verloes, Marco Tartaglia, Valentina Pinna, Gülen Eda Utine, Pelin Ozlem Simsek-Kiper, Elif Yilmaz Gulec, Birute Burnyte, Yoann Vial, Milena Stoyanova, Julia Brinkmann, Francesca Romana Lepri, Alessandro De Luca, Martin Zenker, Marketa Havlovicova, Paola Daniele, Goran Cuturilo, Hélène Cavé, and Dieter Kotzot
Subjects: Genetics, Clinical significance, Genetic heterogeneity, Noonan Syndrome, Biology, RASopathy, medicine.disease, biology.organism_classification, Brief Communication, A2ML1, Phenotype, Mutation, medicine, Noonan syndrome, Missense mutation, Humans, alpha-Macroglobulins, Genetic Testing, 610.72, RASopathies, Gene, Zebrafish, Genetics (clinical)
Abstract: The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.
Published: 2020

23. Author response for 'LEF1 haploinsufficiency causes ectodermal dysplasia'

Author: Isabelle Bailleul-Forestier, Joris Vermeesch, Yline Capri, Anne-Claude Tabet, Koen Devrient, Jonathan I. Levy, Alain Verloes, Myriam Rachid, and Céline Dupont
Subjects: Pathology, medicine.medical_specialty, Ectodermal dysplasia, business.industry, medicine, Haploinsufficiency, medicine.disease, business
Published: 2020
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24. Author response for 'Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction'

Author: Philippine Garret, Blandine Dozières-Puyravel, Alain Verloes, Elke Krüger, Yannis Duffourd, Barbara A. Zieba, Frédéric Ebstein, Christel Thauvin-Robinet, Sana Mahmoudi, Laurence Duplomb, Stéphane Auvin, Sandro Klafack, Geoffroy Delplancq, Antonio Vitobello, Detlef Trost, Jean-Marc Costa, Karun K. Singh, Aïcha Boughalem, and Laurence Faivre
Subjects: Proteasome, business.industry, Epileptic encephalopathy, Medicine, Bioinformatics, business
Published: 2020
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25. Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

Author: Christiane Zweier, Jamal Ghoumid, Cornelia Kraus, Sophie Nambot, Laurence Faivre, Antonio Vitobello, Stéphanie Moortgat, Thierry Bienvenu, Christel Thauvin-Robinet, Virginie Carmignac, Benjamin Cogné, Frédéric Tran Mau-Them, Julien Thevenon, Patrick Callier, Alain Verloes, Christophe Philippe, Sophie Naudion, Renaud Touraine, André Reis, Arthur Sorlin, Caroline Thuillier, Bruno Delobel, Thibaud Jouan, Francis Ramond, Cécile Zordan, Daphné Lehalle, Valérie Benoit, Yannis Duffourd, Mathilde Nizon, Emilie Tisserant, and Thomas Smol
Subjects: 0301 basic medicine, Proband, Adult, Male, Heterozygote, X-linked intellectual disability, Genetic counseling, Disease, 030105 genetics & heredity, Biology, Short stature, 03 medical and health sciences, Young Adult, Genes, X-Linked, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, 10. No inequality, Exome, Genetics (clinical), Histone Demethylases, Epilepsy, Genetic heterogeneity, Genetic Variation, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, Child, Preschool, Mental Retardation, X-Linked, Female, medicine.symptom
Abstract: X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.
Published: 2020

26. Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders

Author: Francesca Clementina Radio, Bruno Dallapiccola, Mélanie Fradin, Alessandra Renieri, Alain Verloes, Jill Clayton-Smith, Michael Smith, Bronwyn Kerr, Rasika Sowmyalakshmi, Dorica Dan, Matteo Cassina, Massimiliano Rossi, Marketa Havlovicova, Laurence Faivre, Con Hennessy, Sofia Douzgou, Hany Mina, Siddharth Banka, Rasa Traberg, Aurélien Trimouille, Myfanwy Rawson, Ruta Marcinkute, Elizabeth Alexander, Ann Nordgren, Adela Chirita Emandi, Florence Riccardi, Jason Gavin, and Lianne Gompertz
Subjects: medicine.medical_specialty, Telemedicine, Service (systems architecture), Developmental disorders, European reference network, Rare disease, Process (engineering), Developmental Disabilities, lcsh:Medicine, Telehealth, behavioral disciplines and activities, Rare Diseases, Intellectual disability, medicine, Humans, Data Protection Act 1998, Pharmacology (medical), Child, Genetics (clinical), Research, lcsh:R, General Medicine, medicine.disease, Patient management, Europe, Medical genetics, Medical emergency, Psychology, Delivery of Health Care
Abstract: Background The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. Results ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. Conclusions We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.
Published: 2020
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27. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

Author: Anita Rauch, Nathalie Pouvreau, Séverine Drunat, Yves Alembik, Anais Ernault, Liza Vera, Hala Nasser, Katharina Steindl, Fabien Guimiot, Pierre Gressens, Vincent El Ghouzzi, Sophie Guilmin Crepon, Delphine Héron, Nathalie Kubis, Alain Verloes, Natacha Teissier, Marie Laure Moutard, Sandrine Passemard, Florentia Kaguelidou, Alexandra Afenjar, Paolo Milani, Marcella Zollino, Pascaline Letard, Martha Momtchilova, Monique Elmaleh-Bergès, University of Zurich, Passemard, Sandrine, Service d'imagerie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Medical Genetics, Hôpitaux Universitaires de Strasbourg, Service de Neurologie Pédiatrique, HFME, Bron, France, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Istituto di Genetica Medica, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Institute of Medical Genetics, University of Zürich [Zürich] (UZH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Universität Zürich [Zürich] = University of Zurich (UZH)
Subjects: Microcephaly, Pathology, medicine.medical_specialty, 2716 Genetics (clinical), 10039 Institute of Medical Genetics, [SDV]Life Sciences [q-bio], CDK5RAP2, intellectual disability, MCPH, primary microcephaly, retinal alteration, sensorineural hearing loss, 610 Medicine & health, Settore MED/03 - GENETICA MEDICA, Microphthalmia, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Holoprosencephaly, 1311 Genetics, Genetics, medicine, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Cochlea, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Retinal, medicine.disease, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Brain size, 570 Life sciences, biology, Sensorineural hearing loss, business, 030217 neurology & neurosurgery
Abstract: BackgroundPrimary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.Methods7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.ResultsAll patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.ConclusionThis is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.Trial registration numberNCT01565005.
Published: 2020
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28. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Author: Jennifer Tarpinian, Alberto Fernández-Jaén, Deborah A. Nickerson, Michael J. Bamshad, Kosuke Izumi, Giovanni Battista Ferrero, Emma Bedoukian, Marcello Niceta, Brendan Lee, A. Micheil Innes, Yuri A. Zarate, Katherine A. Bosanko, Annie Laquerrière, Jennifer A. Bassetti, David Mowat, Beth Keena, Carolina Galaz-Montoya, Claudia Gonzaga-Jauregui, Boris Keren, Reid Sutton, Elaine H. Zackai, James R. Lupski, Constance F. Wells, Francesca Clementina Radio, Natalie Hauser, Dong Li, Grace U Ediae, Marco Tartaglia, Xiang-Jiao Yang, Para Chottil Soumya, Elizabeth J. Bhoj, Christine Coubes, Kinattinkara R. Subbaraman, Alain Verloes, Klaus Dieterich, John C. Carey, Mary K. Kukolich, Francisco Cammarata-Scalisi, Alper Gezdirici, Jessica X. Chong, Sirinart Molidperee, Amelle Shillington, Sarah L. Sawyer, David S. Liu, Ana Bracho, Li Xin Zhang, Richard A. Gibbs, Sheela Nampoothiri, Ingrid A. Holm, Philip M. Boone, Alyssa Ritter, Charlotte Dubucs, Philippe M. Campeau, Gabrielle Lemire, Maria Lisa Dentici, Jacqueline Aziza, Frank J. Probst, Karippoth Mohandas Nair, Millan S. Patel, and Chester W. Brown
Subjects: 0301 basic medicine, Say–Barber–Biesecker–Young–Simpson syndrome, 030105 genetics & heredity, Blepharophimosis, Bioinformatics, KAT6B, Article, 03 medical and health sciences, genitopatellar syndrome, KAT6B disorders, SBBYSS, Intellectual Disability, Genotype, Medicine, Humans, Allele, Increased nuchal translucency, Genetics (clinical), Histone Acetyltransferases, Optic nerve hypoplasia, Polydactyly, business.industry, Enfermedades genéticas congénitas, Pediatría, Embriología, Cystic hygroma, Exons, medicine.disease, Genética, 030104 developmental biology, Intestinal malrotation, Mutation, Genitopatellar syndrome, business
Abstract: Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM
Published: 2020

29. Management of cardiac aspects in children with Noonan syndrome – results from a European clinical practice survey among paediatric cardiologists

Author: Thomas Edouard, Marco Tartaglia, Guftar Shaikh, Martin Zenker, Jan Lebl, Cordula M Wolf, Sixto García-Miñaur, Ingegerd Östman-Smith, Alain Verloes, and Emma Burkitt-Wright
Subjects: Heart Defects, Congenital, Pediatrics, medicine.medical_specialty, Heart disease, Specialty, Sudden cardiac death, Cardiologists, Pharmacotherapy, Surveys and Questionnaires, Genetics, medicine, Humans, Genetic Testing, Practice Patterns, Physicians', Child, Contraindication, Genetics (clinical), Human Growth Hormone, business.industry, Noonan Syndrome, Hypertrophic cardiomyopathy, General Medicine, medicine.disease, Cohort, Noonan syndrome, business
Abstract: BACKGROUND The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated
Published: 2022
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30. Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Author: Isabelle Oliver, Sophie Moniez, Safouane M. Hamdi, Gwenaelle Diene, Audrey Cartault, Béatrice Jouret, Maithé Tauber, Catherine Pienkowski, Myriam Daudin, Jean-Pierre Salles, Benoit Lepage, Thomas Edouard, Alain Verloes, Hélène Cavé, and Armelle Yart
Subjects: Adult, Anti-Mullerian Hormone, Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Context (language use), Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Testis, Humans, Medicine, Inhibins, Child, education, Testosterone, Retrospective Studies, Azoospermia, education.field_of_study, Sertoli Cells, Leydig cell, Sertoli Cell-Only Syndrome, business.industry, Noonan Syndrome, Infant, General Medicine, medicine.disease, Sertoli cell, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, Noonan syndrome, business, Hormone
Abstract: Context Abnormalities in the hypothalamo–pituitary–gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children. Objective The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design It is a retrospective chart review. Patients and methods A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4–15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = −0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: −0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: −1.1 ± 1.2; P NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.
Published: 2018
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31. EFNB2haploinsufficiency causes a syndromic neurodevelopmental disorder

Author: G. Casu, Alain Verloes, N. Marziliano, Brigitte Benzacken, D. Haye, Pierre Gressens, Fabien Guimiot, J. Lévy, Eva Pipiras, Anne-Claude Tabet, C. Dupont, and N. Teissier
Subjects: Male, 0301 basic medicine, Hearing loss, Chromosome Disorders, Ephrin-B2, Haploinsufficiency, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Vasculogenesis, Intellectual disability, Genetics, medicine, Humans, Genetic Association Studies, Genetics (clinical), Chromosomes, Human, Pair 13, business.industry, Infant, Newborn, Infant, medicine.disease, Subtelomere, Pedigree, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Myoclonic epilepsy, Erythropoiesis, Female, Chromosome Deletion, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay. One of the affected sibs further had myoclonic epilepsy and bilateral sensorineural hearing loss. The carrier mother was apparently asymptomatic. Because EFNB2 is located in the subtelomeric region of 13q chromosome, we reviewed the previous reports of terminal 13q deletion. We suggest that haploinsufficiency of the EFNB2 could be at the origin of several clinical features reported in 13qter deletions, including intellectual disability, seizures, congenital heart defects, anorectal malformation and hearing loss.
Published: 2018
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32. Lissencephaly, Genetics of

Author: François Chalard, Pierre Gressens, Alain Verloes, and Sandrine Passemard
Subjects: Genetics, Microcephaly, Microlissencephaly, Cobblestone Lissencephaly, Lissencephalies, Abnormal cortical layering, Neuronal migration, medicine, Lissencephaly, MULTIPLE MALFORMATIONS, Psychology, medicine.disease, Neuroscience
Abstract: The term lissencephaly (literally ‘smooth brain’) covers rare malformations which have in common a reduction of the cortical gyration and an abnormal cortical layering. Different forms of lissencephalies have been described: classical lissencephalies (also called type I) and its variants, and cobblestone lissencephalies (also called type II). Classical lissencephalies include lissencephalies with abnormalities in genes LIS1, DCX or ARX, isolated lissencephalies without any identified genetic defect, lissencephalies with severe microcephaly (microlissencephaly), and lissencephalies associated with syndromes of multiple malformations. The cobblestone lissencephaly is observed in three related syndromes: Walker–Warburg, Fukuyama and muscle-eye-brain (MEB) syndromes. Keywords: neuronal migration; nucleokinesis; LIS1; DCX
Published: 2018
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33. Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia

Author: Edward Blair, Chloé Quélin, Geneviève Baujat, Yline Capri, Sylvie Odent, Pelin Ozlem Simsek-Kiper, Arnold Munnich, Ravi Savarirayan, Caroline Michot, Alice Goldenberg, Stanislas Lyonnet, Valérie Cormier-Daire, Esther Kinning, Carine Le Goff, Bertrand Isidor, Alain Verloes, Brigitte Gilbert-Dussardier, Hülya Kayserili, Martine Le Merrer, Miranda Splitt, Marleen Simon, Patricia Blanchet, Alex Henderson, Judith M.A. Verhagen, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, CHU Rouen, Normandie Université (NU), Northern Genetics Service, Newcastle University [Newcastle], Istanbul University, 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), Hacettepe University Faculty of Medicine, University Medical Center [Utrecht], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Clinical Genetics, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], 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 ), and 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 )
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Pediatrics, medicine.medical_specialty, Adolescent, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Acrodysostosis, Osteochondrodysplasias, Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Knee, Child, PRKAR1A, Genetics (clinical), Hand deformity, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Brachydactyly, Dysostoses, Heterozygote advantage, Syndrome, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 4, 3. Good health, Phenotype, 030104 developmental biology, Dysplasia, Mutation, Female, medicine.symptom, business, Epiphyses, Hand Deformities, Congenital, Exostoses, Multiple Hereditary, 030217 neurology & neurosurgery
Abstract: International audience; Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
Published: 2018
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34. Phosphoglycerate dehydrogenase (PHGDH) deficiency without epilepsy mimicking primary microcephaly

Author: Rémi Kom, Alain Verloes, Damien Haye, Antoine Poli, Catherine Delanoë, Narcisse Elanga, Manuel Schiff, Sandrine Passemard, Séverine Drunat, Yoann Vial, Hala Nasser, Anne Favre, and Emma Cuadro
Subjects: 0301 basic medicine, Genetics, Pediatrics, medicine.medical_specialty, Biology, Drug Resistant Epilepsy, medicine.disease, Compound heterozygosity, 03 medical and health sciences, Epilepsy, 030104 developmental biology, 0302 clinical medicine, PHGDH Gene, medicine, Progressive spasticity, Phosphoglycerate dehydrogenase, Exome, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing
Abstract: Phosphoglycerate dehydrogenase (PHGDH) deficiency (OMIM 256520) is a rare autosomal recessive disorder of serine synthesis, with mostly severe congenital microcephaly, caused by mutations in the PHGDH gene. Fourteen patients reported to date show severe, early onset, drug resistant epilepsy. In a cohort of patients referred for primary microcephaly, compound heterozygosity for two unreported variants in PHGDG was identified by exome sequencing in a pair of sibs who died aged 4.5 months and 4.5 years. They had severe neurological involvement with congenital microcephaly, disorganized EEG, and progressive spasticity, but never had seizures. Exome usage in clinical practice is likely to lead to an expansion of the clinical spectrum of known disorders.
Published: 2017
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35. Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator

Author: Toni Kasole Lubala, A Lulebo Mampasi, T.J.L. de Ravel, Gerrye Mubungu, Leon Mutesa, Jeroen Breckpot, Nono Mvuama, Sébastien Mbuyi-Musanzayi, Nele Cosemans, G Van Buggenhout, Aimé Lumaka, Koenraad Devriendt, Hilde Peeters, Alain Verloes, Maureen Holvoet, Dian Donnai, and P. Lukusa Tshilobo
Subjects: 0301 basic medicine, Down syndrome, business.industry, Ethnic group, Computer based, 030105 genetics & heredity, medicine.disease, 03 medical and health sciences, Facial dysmorphism, 030104 developmental biology, Cohen's kappa, Intellectual disability, Genetics, Medicine, Young adult, Set (psychology), business, Genetics (clinical), Clinical psychology
Abstract: The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with intellectual disability (ID). First, 10 experienced clinicians (five from Africa and five from Europe) rated gestalt in 127 African non-Down Syndrome (non-DS) patients using either the score 2 for ‘clearly dysmorphic’, 0 for ‘clearly non dysmorphic’ or 1 for ‘uncertain’. The inter-rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters (kappa-coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome (DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80%) compared to African (36.8%). We trained the Face2Gene with a set of African DS and non-DS photographs. Interestingly, the recognition in African increased to 94.7%. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic.
Published: 2017
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36. Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS

Author: Y Perdomo-Trujillo, Bart P. Leroy, Benoit Arveiler, Patricia Fergelot, Nursel Elcioglu, Claudio Plaisant, Josseline Kaplan, Fanny Morice-Picard, Vincent Michaud, Eulalie Lasseaux, Pierre-Simon Jouk, Alain Verloes, Didier Lacombe, and Christian P. Hamel
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, HPS5, Dermatology, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Pulmonary fibrosis, medicine, Animals, Humans, Child, Aged, Hypopigmentation, Genetics, integumentary system, business.industry, Infant, Middle Aged, medicine.disease, Oculocutaneous albinism, eye diseases, Bleeding diathesis, 030104 developmental biology, Oncology, Hermanski-Pudlak Syndrome, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Albinism, Female, Hermansky–Pudlak syndrome, medicine.symptom, business
Abstract: Hermansky-Pudlak syndrome (HPS), first described in 1959, is a rare form of syndromic oculocutaneous albinism associated with bleeding diathesis and in some cases pulmonary fibrosis and granulomatous colitis. All 10 HPS types are caused by defects in vesicle trafficking of lysosome-related organelles (LRO) proteins. The HPS5 protein associates with HPS3 and HPS6 to form the biogenesis of lysosome-related organelles complex-2 (BLOC-2). Here, we report the clinical and genetic data of 11 patients with HPS-5 analyzed in our laboratory. We report 11 new pathogenic variants. The 11 patients present with ocular features that are typical for albinism, with mild hypopigmentation, and with no other major complication, apart from a tendency to bleed. HPS-5 therefore appears as a mild form of HPS, which is often clinically undistinguishable from mild oculocutaneous or ocular forms of albinism. Molecular analysis is therefore required to establish the diagnosis of this mild HPS form, which has consequences in terms of prognosis and of clinical management of the patients.
Published: 2017
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37. LEF1 haploinsufficiency causes ectodermal dysplasia

Author: Céline Dupont, Isabelle Bailleul-Forestier, Anne-Claude Tabet, Joris Vermeesch, Yline Capri, Alain Verloes, Myriam Rachid, Jonathan Levy, and Koen Devriendt
Subjects: 0301 basic medicine, Adult, Male, Ectodermal dysplasia, animal structures, Lymphoid Enhancer-Binding Factor 1, Mesenchyme, Ectoderm, Oligodontia, Haploinsufficiency, 030105 genetics & heredity, Biology, 03 medical and health sciences, Mice, Young Adult, Ectodermal Dysplasia, Genetics, medicine, Animals, Humans, Hypohidrotic ectodermal dysplasia, Genetics (clinical), beta Catenin, Ectodermal Dysplasia 1, Anhidrotic, Wnt signaling pathway, NF-kappa B, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, embryonic structures, Cancer research, Hypotrichosis, Female, Signal Transduction
Abstract: Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF-κB or the Wnt/β-catenin pathways. Both pathways are involved in signal transduction from ectoderm to mesenchyme during the development of ectoderm-derived structures. Wnt/β-catenin pathway requires the lymphoid enhancer-binding factor 1 (LEF1), a nuclear mediator, to activate target gene expression. In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. We report two unrelated patients with 4q25 de novo deletion encompassing LEF1, associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. Taurodontism and a particular alveolar bone defect were also observed in both patients. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human. We provide further evidence for LEF1 haploinsufficiency role in ectodermal dysplasia and delineate its clinical phenotype.
Published: 2019

38. VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Author: Séverine Drunat, Yoann Vial, Janvier Hitayezu, Annette Uwineza, Stephane Wenric, Sandrine Passemard, Alain Verloes, Vincent El Ghouzzi, Vincent Bours, Jean-Hubert Caberg, Leon Mutesa, Service de génétique, CHU du Sart-Tilman, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-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) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Microcephaly, VPS51, Endosome, Vesicular Transport Proteins, Postnatal microcephaly, Endosomes, Biology, Nervous System Malformations, 03 medical and health sciences, EARP, 0302 clinical medicine, GARP, Dandy–Walker syndrome, Absent speech, Intellectual disability, Genetics, medicine, Golgi, Humans, Child, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Golgipathies, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders, Rwanda, Brain, General Medicine, medicine.disease, Protein Transport, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cerebellar atrophy, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, trans-Golgi Network
Abstract: International audience; Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.
Published: 2019
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39. Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Stephan Kemeny, Sandrine Passemard, Sandra Chantot-Bastaraud, Chloé Quélin, Laurence Perrin, Julien Buratti, Patrick Edery, Céline Dupont, Chantal Missirian, Philippe Vago, Alexandra Afenjar, Marie-Laure Vuillaume, Yline Capri, Klaus Dieterich, Laila El Khattabi, Charles Coutton, Françoise Devillard, Annick Toutain, Alain Verloes, Nicole Philip, Hubert Journel, Véronique Satre, Marie Ducloy, Delphine Héron, Richard Delorme, Cédric Le Caignec, Anne-Claude Tabet, Damien Sanlaville, Isabelle Marey, Laurence Faivre, Christèle Dubourg, Anne-Laure Mosca-Boidron, Laetitia Gouas, Abdelamdjid Benmansour, Jean Chiesa, Séverine Drunat, Cyril Mignot, Aurélia Jacquette, Boris Keren, Claire S. Leblond, Claire Beneteau, Brigitte Benzacken, Vincent Gatinois, Olivier Pichon, Damien Haye, Roberto Toro, Sandra Whalen, Dominique Martin, Thomas Rolland, Thomas Bourgeron, Albert David, Alexandre Mathieu, Mélanie Fradin, Frédérique Amsellem, Bertrand Isidor, James Lespinasse, Caroline Rooryck, Jacques Puechberty, Eva Pipiras, Lucile Pinson, Didier Lacombe, Jonathan M. Levy, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU de Lyon, Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de Chambéry (C.H.de Chambéry), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), AP-HP Hôpital universitaire Robert-Debré [Paris], Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, UF de Cytogénétique, Institut Pasteur [Paris], Université de Bordeaux (UB), École normale supérieure - Rennes (ENS Rennes), Unité de Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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) (APHP)-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), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Gatonero SA, Hôtel-Dieu de Nantes, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, CHU Clermont-Ferrand-Hôpital d'Estaing, 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), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des anomalies du développement [Lyon], UF de Biochimie et Génétique Moléculaire (BGM), 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), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), IMAXIO, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-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 de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, 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 de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Bretagne Atlantique [Vannes], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), 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), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Rolland, Thomas
Subjects: medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Phelan-McDermid syndrome, Genetics, medicine, 0501 psychology and cognitive sciences, In patient, Clinical genetics, Author Correction, Psychiatry, Molecular Biology, Genetics (clinical), business.industry, lcsh:R, Neurodevelopmental disorders, 05 social sciences, lcsh:Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract: Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders., The underlying genetics of Phelan-McDermid syndrome Multiple chromosomal changes may impact the severity of symptoms in people with Phelan-McDermid syndrome (PMS). Thomas Bourgeron of the Institut Pasteur and colleagues in France conducted genomic analyses and explored the clinical features of 85 people with PMS, a condition caused by a deletion in the long arm of chromosome 22. It is often associated with severe symptoms such as intellectual disability, autism, and seizures. The chromosomal changes in 65% of those studied were not inherited. MRI brain scans showed visible abnormalities in 23 of 35 patients imaged. The size of the chromosomal deletion varied. Patients with small deletions were more likely to have autistic symptoms while those with large deletions were more likely to be unable to talk. The team also identified genes in chromosome 22 and in other regions of the genome that could modify the severity of PMS symptoms.
Published: 2019
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40. Dermatological manifestations in Noonan syndrome

Author: Yline Capri, Emmanuelle Bourrat, Federico Manna, Sophie Guillaumont, Claire Jeandel, Pierre Sarda, Valérie Pallure, C. Abadie, Stéphanie Mallet, P. Blanchet, J. Miquel, F. Giuliano, Nicolas Molinari, Clarisse Baumann, C. Pernet, Hélène Cavé, Fanny Morice-Picard, Smail Hadj-Rabia, Lucile Pinson, David Geneviève, M. Best, M.‐L. Jacquemont, Sabine Sigaudy, Christine Coubes, Christine Chiaverini, M. Willems, Juliette Mazereeuw-Hautier, Alain Verloes, Didier Bessis, Didier Lacombe, A.-C. Bursztejn, Nicole Philip, and Yoann Vial
Subjects: medicine.medical_specialty, business.industry, Medicine, Noonan syndrome, Dermatology, business, medicine.disease
Published: 2019
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41. Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder

Author: Sylvie Tordjman, Patrick Edery, Renaud Touraine, Audrey Labalme, Nicolas Chatron, Caroline Schluth-Bolard, Pierre Antoine Rollat-Farnier, Alain Verloes, Brigitte Gilbert-Dussardier, Damien Sanlaville, Massimiliano Rossi, Gaetan Lesca, Fabienne Giuliano, Julie Masson, Giuseppe Testa, and Caroline Demily
Subjects: Adult, Male, Williams Syndrome, 0301 basic medicine, Hypersociability, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, DNA Copy Number Variations, Autism Spectrum Disorder, Population, lcsh:Medicine, 030105 genetics & heredity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Intellectual disability, Humans, Williams Beuren syndrome, Medicine, Pharmacology (medical), GTF2I, cardiovascular diseases, Copy-number variation, Child, education, Letter to the Editor, Genetics (clinical), Exome sequencing, Genetics, education.field_of_study, business.industry, lcsh:R, Whole exome sequencing, General Medicine, medicine.disease, Human genetics, 3. Good health, Phenotype, Autism spectrum disorder, Autism, Female, Chromosome Deletion, business, 030217 neurology & neurosurgery, 7q11.23 microdeletion
Abstract: Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit. Electronic supplementary material The online version of this article (10.1186/s13023-019-1094-5) contains supplementary material, which is available to authorized users.
Published: 2019
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42. Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation‐positive patients

Author: N. Pouvreau, F. Giuliano, Smail Hadj-Rabia, M.‐L. Jacquemont, Emmanuelle Bourrat, Juliette Mazereeuw-Hautier, Yline Capri, Didier Lacombe, F. Morice‐picard, Christine Chiaverini, Cédric Baumann, Didier Bessis, J. Miquel, Pierre Sarda, M. Best, Nicole Philip, Yoann Vial, C. Abadie, Alain Verloes, Safa Aouinti, Lucile Pinson, C. Pernet, Sabine Sigaudy, Stéphanie Mallet, David Geneviève, Christine Coubes, Anne-Claire Bursztejn, Nicolas Molinari, Hélène Cavé, Béatrice Parfait, Stanislas Lyonnet, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU de Bordeaux Pellegrin [Bordeaux], Hôpital Robert Debré Paris, Hôpital Robert Debré, CHU Pontchaillou [Rennes], Hôpital de la Colombière, 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 Régional Universitaire de Nancy (CHRU Nancy), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Necker - Enfants Malades [AP-HP], CHU Sud Saint Pierre [Ile de la Réunion], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR), Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Michel-Avella, Amandine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), CHU Toulouse [Toulouse], Université de Rennes (UNIV-RENNES), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Heart Defects, Congenital, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Adolescent, MAP Kinase Kinase 2, MAP Kinase Kinase 1, Administration, Oral, Dermatology, Cardiofaciocutaneous syndrome, Administration, Cutaneous, Keratosis Pilaris, Acitretin, Diagnosis, Differential, 030207 dermatology & venereal diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Costello syndrome, Ectodermal Dysplasia, Medicine, Humans, Prospective Studies, Young adult, Prospective cohort study, Child, Genetic Association Studies, Sirolimus, Palmoplantar hyperkeratosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Costello Syndrome, Noonan Syndrome, Facies, medicine.disease, 3. Good health, Failure to Thrive, Treatment Outcome, Child, Preschool, Mutation, Noonan syndrome, Female, France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.
Published: 2019
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43. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Author: Hélène Cavé, Nicole Philip, Christine Chiaverini, M.‐L. Jacquemont, Emmanuelle Bourrat, Valérie Pallure, J. Miquel, Juliette Mazereeuw-Hautier, Clarisse Baumann, Yline Capri, Stéphanie Mallet, Sophie Guillaumont, Federico Manna, Claire Jeandel, Smail Hadj-Rabia, Yoann Vial, C. Pernet, Pierre Sarda, M. Willems, Lucile Pinson, C. Abadie, Sabine Sigaudy, Christine Coubes, F. Giuliano, Didier Lacombe, Fanny Morice-Picard, P. Blanchet, Didier Bessis, David Geneviève, M. Best, Alain Verloes, A.-C. Bursztejn, Nicolas Molinari, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Physique Théorique et Astroparticules (LPTA), Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Met Office Hadley Centre, Joint Centre for Hydrometeorological Research, Wallingford, United Kingdom, ONERA - The French Aerospace Lab [Châtillon], ONERA, Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Saint-Pierre Institute, Service de dermatologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Production du lait (PL), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Service de dermatologie (CHU de Toulouse), CHU Toulouse [Toulouse], Centre Hospitalier Saint Jean de Perpignan, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Interactions et dynamique des environnements de surface (IDES), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Joint Centre for Hydro-Meteorological Research, Met Office Hadley Centre (JCHMR), United Kingdom Met Office [Exeter], ONERA-Université Paris Saclay (COmUE), 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)-CHU Necker - Enfants Malades [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 de la Timone [CHU - APHM] (TIMONE), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: musculoskeletal diseases, Neuroblastoma RAS viral oncogene homolog, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Dermatology, medicine.disease_cause, Keratosis Pilaris, Skin Diseases, 030207 dermatology & venereal diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, Humans, Prospective Studies, skin and connective tissue diseases, Child, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Aged, Univariate analysis, Mutation, business.industry, Noonan Syndrome, Multiple Lentigines, Infant, Middle Aged, medicine.disease, 3. Good health, PTPN11, medicine.anatomical_structure, Phenotype, Scalp, Child, Preschool, Noonan syndrome, Female, business
Abstract: BACKGROUND Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and cafe-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.
Published: 2019
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44. Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly

Author: Joana Figueiro-Silva, Reza Asadollahi, Ratna Dua Puri, Heinrich Sticht, Lance H. Rodan, Michael Papik, Beatrice Oneda, Anselm H. C. Horn, Sharyn A. Lincoln, Paranchai Boonsawat, Katharina Steindl, Ishwar C. Verma, Beatrice Latal, Laura Gogoll, Anita Rauch, Pascal Joset, Séverine Drunat, Oskar G. Jenni, Dunja Niedrist, Frenny Sheth, Markus Zweier, Alain Verloes, Robert Steinfeld, Dennis Kraemer, Chaitanya Datar, Barbara Plecko, Silvia Azzarello-Burri, Marcella Zollino, Ruxandra Bachmann-Gagescu, Rahim Masood, and Sandrine Passemard
Subjects: Male, Microcephaly, Candidate gene, Adolescent, Genetic counseling, Developmental Disabilities, Ubiquitin-Protein Ligases, Cell Cycle Proteins, Biology, Settore MED/03 - GENETICA MEDICA, Article, DEAD-box RNA Helicases, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Child, Gene, QH426, Wnt Signaling Pathway, Exome sequencing, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, MCPH, genetic counseling, Microarray analysis techniques, secondary microcephaly, primary microcephaly, Infant, medicine.disease, Phenotype, 3. Good health, Pedigree, mitochondria, Gene Expression Regulation, Child, Preschool, Mutation, Female, 030217 neurology & neurosurgery
Abstract: Purpose\ud Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.\ud Methods\ud We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).\ud Results\ud We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1).\ud Conclusion\ud Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.
Published: 2019

45. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases

Author: Philippe Loget, Fanny Pelluard, Valérie Goua, Annie Laquerrière, Alain Verloes, Laurence Faivre, P. Dechelotte, Nicole Laurent, Thierry Frebourg, Martine Bucourt, Sophie Blesson, Fabien Guimiot, Martine Maréchaud, Aude Tessier, Charlotte Mechler, J.C. Sabourin, Corinne Jeanne-Pasquier, Marie-Josée Perez, Anne-Marie Guerrot, Sophie Patrier, Alice Goldenberg, Gwenaëlle André, Mélie Sarreau, and Mathilde Lefebvre
Subjects: 0301 basic medicine, Pregnancy, Pathology, medicine.medical_specialty, Omphalocele, Obstetrics, business.industry, Obstetrics and Gynecology, Oligohydramnios, Prenatal diagnosis, 030105 genetics & heredity, medicine.disease, 03 medical and health sciences, 030104 developmental biology, Dysplasia, Agenesis, medicine, Syndactyly, business, Fraser syndrome, Genetics (clinical)
Abstract: Objective Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. Method We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. Results Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). Conclusion This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.
Published: 2016
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46. Failure of ossification of the occipital bone in mandibuloacral dysplasia type B

Author: Jürgen Kohlhase, Jonathan Levy, Dan Lipsker, Véronique Lambert, Frédéric Adjimi, Damien Haye, Mohamed Agha, Hend Dridi, Alain Verloes, and Maurice Lambert
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Ossification, business.industry, Occipital bone, 030105 genetics & heredity, medicine.disease, Short stature, Mandibuloacral dysplasia, 03 medical and health sciences, 030104 developmental biology, Ptosis, Intramembranous ossification, Genetics, medicine, Wormian bones, Lipodystrophy, medicine.symptom, business, Genetics (clinical)
Abstract: Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post-translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12-year-old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy. © 2016 Wiley Periodicals, Inc.
Published: 2016
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47. Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome

Author: C.E.M. de Die-Smulders, Raoul C.M. Hennekam, Audrey Putoux, Alain Verloes, Séverine Drunat, Patrick Edery, Annette Uwineza, F. Champion, A. Besson, J. Michel, Aimee D C Paulussen, Dominique Boggio, Marie-Josée Perez, Sylvie Mazoyer, W.K. van Putten, Gaetan Lesca, Isabella Borg, Y. Musizzano, Damien Sanlaville, Alexandre Vasiljevic, Amerh Alqahtani, Ferechté Razavi, Lucile Pinson, Laurent Guibaud, Eudeline Alix, Sheela Nampoothiri, and Thatjana Gardeitchik
Subjects: 0301 basic medicine, Genetics, Microcephaly, Mutation, Corpus Callosum Agenesis, Mild intrauterine growth retardation, Dwarfism, Biology, Compound heterozygosity, medicine.disease, medicine.disease_cause, Short stature, 03 medical and health sciences, 030104 developmental biology, Minor spliceosome, medicine, medicine.symptom, Genetics (clinical)
Abstract: Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.
Published: 2016
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48. Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome

Author: Natacha Lehman, Didier Lacombe, Delphine Héron, Frédérique Debomy, Sylvie Manouvrier, Frédéric Huet, Patrick Edery, Laurence Faivre, Sylvie Odent, Myriam Mikaty, Jennifer Gallard, Sophie Chancenotte, Sandrine Vinault, Maïté Tauber, David Geneviève, Coralie Rastel, Nicole Philip, Christine Binquet, Mathieu Bordes, Alain Verloes, Jamal Ghoumid, Elodie Gautier, Christel Thauvin-Robinet, Emilie Schmitt, Jenny Cornaton, Marie Bournez, Nolwenn Jean, Catherine Lejeune, Delphine Minot, Alice Masurel, Pierre-Henri Roux-Levy, 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), 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), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), CHU Dijon, Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and CCSD, Accord Elsevier
Subjects: Male, 0301 basic medicine, medicine.medical_treatment, Intellectual disability, MESH: Cognition, CBCL, 030105 genetics & heredity, Cognition, Multidisciplinary approach, MESH: Child, Medicine, Child, Genetics (clinical), Rehabilitation, MESH: Hormone Replacement Therapy, Neurological Rehabilitation, Neuropsychology, Wechsler Adult Intelligence Scale, General Medicine, 3. Good health, MESH: Young Adult, Child, Preschool, Education, Special, Female, France, Prader-Willi Syndrome, Occupational therapy, medicine.medical_specialty, Adolescent, Hormone Replacement Therapy, MESH: Social Support, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Young Adult, 03 medical and health sciences, Social support, MESH: Neurological Rehabilitation, Genetics, Humans, Psychiatry, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Social Support, medicine.disease, MESH: Male, MESH: France, Patient care management, 030104 developmental biology, MESH: Education, Special, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prader-Willi Syndrome, business, MESH: Female
Abstract: International audience; Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
Published: 2020
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49. CBP/EP300-dependent acetylation and stabilization of HSF2 are compromised in the rare disorder, Rubinstein-Taybi syndrome

Author: Carène Benasolo, Élise Lebigot, Jérémy Berthelet, Madeline A. Lancaster, Federico Miozzo, Didier Lacombe, Sarah Naceri, Déborah Bouvier, Olivier Taboureau, Aurélie de Thonel, Johanna K. Ahlskog, Véronique Dubreuil, Mathilde Henry, Pierre Gressens, Sandrine Passemart, Matthieu Sanial, Jean-Paul Concordet, Délara Sabéran-Djoneidi, Patricia Fergelot, Marion Cordonnier, Jessica Gobbo, Mikael C. Puustinen, Anna L. Aalto, Agathe Duchateau, Michel Petitjean, Ryma Abane, Alain Verloes, Lea Sistonen, Carmen Garrido, Valérie Mezger, Sandy D. Westerheide, Anniina Vihervaara, Fernando Rodrigues-Uma, and Geoffrey Pires
Subjects: 0303 health sciences, Chemistry, In silico, Human brain, HDAC1, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Proteostasis, Acetylation, medicine, Heat shock, EP300, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SUMMARYCells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex and required for brain development. Here, we reveal that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. Using unbiased, biochemical, cell-imaging, and in silico approaches, we show that CBP/EP300 acetylates HSF2 at specific lysine residues, which promotes HSF2 stabilization, whereas the lysine deacetylase HDAC1 catalyzes its proteasomal degradation. The CBP KIX domain and KlX-recognizing motifs in HSF2 are critical for its interaction with acetylating enzymes. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutated CBP or EP300. We show that RSTS patient cells exhibit decreased HSF2 levels and impaired heat shock response. The dysregulated HSF pathway in RSTS opens new avenues for understanding the molecular basis of this multifaceted pathology.
Published: 2018
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50. PEDIA: Prioritization of Exome Data by Image Analysis

Author: Eamonn Sheridan, Alfredo Orrico, Ivan Ivanovski, Saskia Biskup, Alexej Knaus, Marzena Wiśniewska, Anna Keryan, Bernd Wollnik, Gundula Thiel, Gorazd Rudolf, Max Zhao, Malte Spielmann, Yaron Gurovich, Sandra Wilson, Uwe Kornak, Pola Smirin-Yosef, Yair Hanani, Christina Fagerberg, Christian Thiel, Peter N. Robinson, Diana Mitter, Annick Raas-Rothschild, Gholson J. Lyon, Na Zhu, Dagmar Wahl, Nechama Haddad, Claus-Eric Ott, Antonio Martinez Carrascal, Janelle Howell, Nadja Ehmke, Irena Vrecar, Purificación Marín Reina, Oleg V. Borisov, Konstanze Hoertnagel, Denise Horn, Nurulhuda Hajjir, Sabine Rudnik, Sebastian Köhler, Marie Coutelier, Nicole Revencu, Ingrid Weber, Stanislav Rosnev, Johannes Zschocke, Claudia Ciaccio, Or Shanoon, Nicole Fleischer, Anna Schossig, Luitgard Graul-Neumann, Guy Nadav, Dione Aguilar, Susanne B. Kamphausen, Markus M. Nöthen, Allan Bayat, Borut Peterlin, Heidi Beate Bentzen, Øivind Braaten, Eun Kyung Suk, Magdalena Danyel, Ming W. Yeung, Catherine Karimov, Angela M. Kaindl, Luis Becerra-Solano, Tzung-Chien Hsieh, Svenja Daschkey, Laura Morlan Herrador, Christine Fauth, Stefan Mundlos, Ulrich A. Schatz, Jean Tori Pantel, Alain Verloes, Heinz Gabriel, Kirsten Cremer, Alexander Lavrov, Karen W. Gripp, Martin A. Mensah, Kristen Park, Yves Sznajer, Jakob Hertzberg, Korina Winter, Max Schubach, Sofia Douzgou, Peter Krawitz, Hadil Kathom, Linda M. Randolph, Björn Fischer-Zirnsak, Maximilian Leitheiser, Tom Kamphans, Asya Gusina, Omri Bar, Hilda David Eden, Koenraad Devriendt, Dejan Đukić, Elisabeth Mangold, Laura Pölsler, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: Male, 0301 basic medicine, Computer science, 030105 genetics & heredity, computer.software_genre, computer vision, Databases, Genetic, Image Processing, Computer-Assisted, Exome, Genetics (clinical), Exome sequencing, variant prioritization, 0303 health sciences, 030305 genetics & heredity, dysmorphology, Genomics, 3. Good health, Phenotype, Cohort, Medical genetics, Female, exome diagnostics, Algorithms, Natural language processing, deep learning, Prioritization, medicine.medical_specialty, Article, Image (mathematics), 03 medical and health sciences, Similarity (network science), Similarity (psychology), medicine, Humans, Gene, 030304 developmental biology, business.industry, Deep learning, Computational Biology, Sequence Analysis, DNA, 030104 developmental biology, Artificial intelligence, business, computer, Software
Abstract: PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2807-2814 ispartof: location:United States status: published
Published: 2018
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