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1. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Author

Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree DeMille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E. L. M. Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M. Butler, Michael J. Lyons, Claudia M. B. Carvalho, Chaofan Zhang, James R. Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane McCormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K. Haanpää, Pia Pohjola, Harri Arikka, Anneke J. A. Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, and Alexandre Reymond

Subjects
Mesomelic dysplasia, Horseshoe kidney, Intellectual disability, Transcriptome, Zebrafish model, Medicine, Genetics, QH426-470
Abstract

Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Published
2024
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2. TAD boundary deletion causes PITX2-related cardiac electrical and structural defects

Author

Manon Baudic, Hiroshige Murata, Fernanda M. Bosada, Uirá Souto Melo, Takanori Aizawa, Pierre Lindenbaum, Lieve E. van der Maarel, Amaury Guedon, Estelle Baron, Enora Fremy, Adrien Foucal, Taisuke Ishikawa, Hiroya Ushinohama, Sean J. Jurgens, Seung Hoan Choi, Florence Kyndt, Solena Le Scouarnec, Vincent Wakker, Aurélie Thollet, Annabelle Rajalu, Tadashi Takaki, Seiko Ohno, Wataru Shimizu, Minoru Horie, Takeshi Kimura, Patrick T. Ellinor, Florence Petit, Yves Dulac, Paul Bru, Anne Boland, Jean-François Deleuze, Richard Redon, Hervé Le Marec, Thierry Le Tourneau, Jean-Baptiste Gourraud, Yoshinori Yoshida, Naomasa Makita, Claude Vieyres, Takeru Makiyama, Stephan Mundlos, Vincent M. Christoffels, Vincent Probst, Jean-Jacques Schott, and Julien Barc

Subjects
Science
Abstract

Abstract While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Published
2024
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3. The Neurod1/4-Ntrk3-Src pathway regulates gonadotrope cell adhesion and motility

Author

Charles Le Ciclé, Vincent Pacini, Nicolas Rama, Servane Tauszig-Delamasure, Eloïse Airaud, Florence Petit, Simon de Beco, Joëlle Cohen-Tannoudji, and David L’hôte

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Pituitary gonadotrope cells are essential for the endocrine regulation of reproduction in vertebrates. These cells emerge early during embryogenesis, colonize the pituitary glands and organize in tridimensional networks, which are believed to be crucial to ensure proper regulation of fertility. However, the molecular mechanisms regulating the organization of gonadotrope cell population during embryogenesis remain poorly understood. In this work, we characterized the target genes of NEUROD1 and NEUROD4 transcription factors in the immature gonadotrope αT3-1 cell model by in silico functional genomic analyses. We demonstrated that NEUROD1/4 regulate genes belonging to the focal adhesion pathway. Using CRISPR/Cas9 knock-out approaches, we established a double NEUROD1/4 knock-out αT3-1 cell model and demonstrated that NEUROD1/4 regulate cell adhesion and cell motility. We then characterized, by immuno-fluorescence, focal adhesion number and signaling in the context of NEUROD1/4 insufficiency. We demonstrated that NEUROD1/4 knock-out leads to an increase in the number of focal adhesions associated with signaling abnormalities implicating the c-Src kinase. We further showed that the neurotrophin tyrosine kinase receptor 3 NTRK3, a target of NEUROD1/4, interacts physically with c-Src. Furthermore, using motility rescue experiments and time-lapse video microscopy, we demonstrated that NTRK3 is a major regulator of gonadotrope cell motility. Finally, using a Ntrk3 knock-out mouse model, we showed that NTRK3 regulates gonadotrope cells positioning in the developing pituitary, in vivo. Altogether our study demonstrates that the Neurod1/4-Ntrk3-cSrc pathway is a major actor of gonadotrope cell mobility, and thus provides new insights in the regulation of gonadotrope cell organization within the pituitary gland.

Published
2023
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4. Multi-classifier prediction of knee osteoarthritis progression from incomplete imbalanced longitudinal data

Author

Widera, Paweł, Welsing, Paco M. J., Ladel, Christoph, Loughlin, John, Lafeber, Floris P. J. G., Dop, Florence Petit, Larkin, Jonathan, Weinans, Harrie, Mobasheri, Ali, and Bacardit, Jaume

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class classification task, with classes based on clinically relevant measures of progression (over a time scale typical for clinical trials). Using data from two long-term knee osteoarthritis studies OAI and CHECK, we tested multiple algorithms and learning process configurations (including multi-classifier approaches, cost-sensitive learning, and feature selection), to identify the best performing machine learning models. We examined the behaviour of the best models, with respect to prediction errors and the impact of used features, to confirm their clinical relevance. We found that the model-based selection outperforms the conventional inclusion criteria, reducing by 20-25% the number of patients who show no progression. This result might lead to more efficient clinical trials., Comment: 22 pages, 12 figures, 10 tables

Published
2019
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5. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool

Author

Frédéric Tran Mau-Them, Julian Delanne, Anne-Sophie Denommé-Pichon, Hana Safraou, Ange-Line Bruel, Antonio Vitobello, Aurore Garde, Sophie Nambot, Nicolas Bourgon, Caroline Racine, Arthur Sorlin, Sébastien Moutton, Nathalie Marle, Thierry Rousseau, Paul Sagot, Emmanuel Simon, Catherine Vincent-Delorme, Odile Boute, Cindy Colson, Florence Petit, Marine Legendre, Sophie Naudion, Caroline Rooryck, Clément Prouteau, Estelle Colin, Agnès Guichet, Alban Ziegler, Dominique Bonneau, Godelieve Morel, Mélanie Fradin, Alinoé Lavillaureix, Chloé Quelin, Laurent Pasquier, Sylvie Odent, Gabriella Vera, Alice Goldenberg, Anne-Marie Guerrot, Anne-Claire Brehin, Audrey Putoux, Jocelyne Attia, Carine Abel, Patricia Blanchet, Constance F. Wells, Caroline Deiller, Mathilde Nizon, Sandra Mercier, Marie Vincent, Bertrand Isidor, Jeanne Amiel, Rodolphe Dard, Manon Godin, Nicolas Gruchy, Médéric Jeanne, Elise Schaeffer, Pierre-Yves Maillard, Frédérique Payet, Marie-Line Jacquemont, Christine Francannet, Sabine Sigaudy, Marine Bergot, Emilie Tisserant, Marie-Laure Ascencio, Christine Binquet, Yannis Duffourd, Christophe Philippe, Laurence Faivre, and Christel Thauvin-Robinet

Subjects
exome sequencing (ES), chromosomal microarray, prenatal, fetal, diagnostic yield, Genetics, QH426-470
Abstract

Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

Published
2023
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6. Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

Author

Delfina M. Romero, Karine Poirier, Richard Belvindrah, Imane Moutkine, Anne Houllier, Anne-Gaëlle LeMoing, Florence Petit, Anne Boland, Stephan C. Collins, Mariano Soiza-Reilly, Binnaz Yalcin, Jamel Chelly, Jean-François Deleuze, Nadia Bahi-Buisson, and Fiona Francis

Subjects
Science
Abstract

The Dlgap protein family members are known for their role in synapses. Here the authors reveal important involvement in earlier steps of brain development, identifying DLGAP4 mutations in patients with cortical malformations, and also demonstrating a role in progenitors and migrating neurons.

Published
2022
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7. Executive functioning in adolescents and adults with Silver-Russell syndrome.

Author

Mélissa Burgevin, Agnès Lacroix, Fanny Ollivier, Karine Bourdet, Régis Coutant, Bruno Donadille, Laurence Faivre, Sylvie Manouvrier-Hanu, Florence Petit, Christel Thauvin-Robinet, Annick Toutain, Irène Netchine, and Sylvie Odent

Subjects
Medicine, Science
Abstract

Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13-39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants' families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS.

Published
2023
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8. Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

Author

Endika Haro, Florence Petit, Charmaine U. Pira, Conor D. Spady, Sara Lucas-Toca, Lauren I. Yorozuya, Austin L. Gray, Fabienne Escande, Anne-Sophie Jourdain, Andy Nguyen, Florence Fellmann, Jean-Marc Good, Christine Francannet, Sylvie Manouvrier-Hanu, Marian A. Ros, and Kerby C. Oberg

Subjects
Science
Abstract

Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.

Published
2021
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9. 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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10. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B. A. De Vries, Lisenka E. L. M. Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, CAUSES Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L. Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E. H. Simon, Koen L. I. van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, SPARK Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, and Evan E. Eichler

Subjects
Neurodevelopmental disorders, hnRNPs, Cortex development, Gene families, Medicine, Genetics, QH426-470
Abstract

Abstract Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021
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11. Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia

Author

Aki Ushiki, Yichi Zhang, Chenling Xiong, Jingjing Zhao, Ilias Georgakopoulos-Soares, Lauren Kane, Kirsty Jamieson, Michael J. Bamshad, Deborah A. Nickerson, University of Washington Center for Mendelian Genomics, Yin Shen, Laura A. Lettice, Elizabeth Lemos Silveira-Lucas, Florence Petit, and Nadav Ahituv

Subjects
Science
Abstract

Acheiropodia is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development, but how these deletions lead to this phenotype is unknown. Here the authors use whole-genome sequencing, ChIP-seq, 4C-seq and DNA FISH to show that alterations in CTCF motifs are responsible via altered enhancer–promoter interactions.

Published
2021
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12. Habenular Neurons Expressing Mu Opioid Receptors Promote Negative Affect in a Projection-Specific Manner

Author

Julie Bailly, Florence Allain, Eric Schwartz, Chloé Tirel, Charles Dupuy, Florence Petit, Marco A. Diana, Emmanuel Darcq, and Brigitte L. Kieffer

Subjects
Article, Biological Psychiatry
Abstract

The mu opioid receptor (MOR) is central to hedonic balance and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states. To investigate this hypothesis, we tested whether neurons expressing MOR in the Hb (Hb-MOR neurons) promote negative affect.Using Oprm1-Cre knockin mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of Hb-MOR neuron stimulation for approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze, and marble burying), and despair-like behavior (tail suspension).Optostimulation of Hb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus, Hb-MOR neurons project to the dorsal raphe nucleus. Optostimulation of Hb-MOR/interpeduncular nucleus terminals triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of Hb-MOR/dorsal raphe nucleus terminals increased levels of anxiety with no effect on other behaviors, revealing 2 dissociable pathways controlling negative affect.Together, the data demonstrate that Hb neurons expressing MOR facilitate aversive states via 2 distinct Hb circuits, contributing to despair-like behavior (Hb-MOR/interpeduncular nucleus) and anxiety (Hb-MOR/dorsal raphe nucleus). The findings support the notion that inhibition of these neurons by either endogenous or exogenous opioids may relieve negative affect, a mechanism that would have implications for hedonic homeostasis and addiction.

Published
2023

13. Identification of a pituitary ERα-activated enhancer triggering the expression of Nr5a1, the earliest gonadotrope lineage-specific transcription factor

Author

Vincent Pacini, Florence Petit, Bruno Querat, Jean-Noël Laverriere, Joëlle Cohen-Tannoudji, and David L’hôte

Subjects
Gonadotrope specification, Enhancer, Epigenetic, Nr5a1, Estrogen receptor, Genetics, QH426-470
Abstract

Abstract Background Gonadotrope lineage differentiation is a stepwise process taking place during pituitary development. The early step of gonadotrope lineage specification is characterized by the expression of the Nr5a1 transcription factor, a crucial factor for gonadotrope cell fate determination. Abnormalities affecting Nr5a1 expression lead to hypogonadotropic hypogonadism and infertility. Although significant knowledge has been gained on the signaling and transcriptional events controlling gonadotrope differentiation, epigenetic mechanisms regulating Nr5a1 expression during early gonadotrope lineage specification are still poorly understood. Results Using ATAC chromatin accessibility analyses on three cell lines recapitulating gradual stages of gonadotrope differentiation and in vivo on developing pituitaries, we demonstrate that a yet undescribed enhancer is transiently recruited during gonadotrope specification. Using CRISPR/Cas9, we show that this enhancer is mandatory for the emergence of Nr5a1 during gonadotrope specification. Furthermore, we identify a highly conserved estrogen-binding element and demonstrate that the enhancer activation is dependent upon estrogen acting through ERα. Lastly, we provide evidence that binding of ERα is crucial for chromatin remodeling of Nr5a1 enhancer and promoter, leading to RNA polymerase recruitment and transcription. Conclusion This study identifies the earliest regulatory sequence involved in gonadotrope lineage specification and highlights the key epigenetic role played by ERα in this differentiation process.

Published
2019
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14. Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature

Author

Chamara Sampath Paththinige, Nirmala Dushyanthi Sirisena, Fabienne Escande, Sylvie Manouvrier, Florence Petit, and Vajira Harshadeva Weerabaddana Dissanayake

Subjects
Ectrodactyly, Split hand/foot malformation, Split hand/foot malformation with long bone deficiency, 17p13.3 duplication, BHLHA9, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. Case presentation The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. Conclusions We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.

Published
2019
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15. Generation of an iPSC line (IMAGINi022-A) from a patient carrying a SOX10 missense mutation and presenting with deafness, depigmentation and progressive neurological impairment

Author

Celine Banal, Eddy Quelennec, William Bertani-Torres, Nadjet Gacem, Jeanne Amiel, Sandrine Marlin, Florence Petit, Veronique Pingault, Nathalie Lefort, and Nadege Bondurand

Subjects
Biology (General), QH301-705.5
Abstract

Mutations of SOX10 result in a broad range of phenotypes including Waardenburg syndrome (WS types 2 and 4) that can be found in association with peripheral demyelinating neuropathy and/or central dysmyelinating leukodystrophy. Here, we generated induced pluripotent stem cells (iPSCs) from a patient carrying a de novo heterozygous missense mutation in the SOX10 gene (MIM* 602229, NM006941.3c.523C > G; p.Pro175Ala) presenting with deafness, depigmentation and progressive neurological impairment. Cells were reprogrammed by non-integrative viral transduction from blood sample, have normal karyotype, express pluripotency markers and are able to differentiate into the three germ cell layers.

Published
2020
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16. Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Author

Claudio Reggiani, Sandra Coppens, Tayeb Sekhara, Ivan Dimov, Bruno Pichon, Nicolas Lufin, Marie-Claude Addor, Elga Fabia Belligni, Maria Cristina Digilio, Flavio Faletra, Giovanni Battista Ferrero, Marion Gerard, Bertrand Isidor, Shelagh Joss, Florence Niel-Bütschi, Maria Dolores Perrone, Florence Petit, Alessandra Renieri, Serge Romana, Alexandra Topa, Joris Robert Vermeesch, Tom Lenaerts, Georges Casimir, Marc Abramowicz, Gianluca Bontempi, Catheline Vilain, Nicolas Deconinck, and Guillaume Smits

Subjects
Functional genomics, Promoters, Neurodevelopmental disorders, Intellectual disability, DLG2, Medicine, Genetics, QH426-470
Abstract

Abstract Background Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Methods Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. Results Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients’ clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. Conclusions While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.

Published
2017
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17. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders

Author

Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, Séverine AUDEBERT-BELLANGER, Catherine Badens, Frédéric Bilan, Varoona Bizaoui, Anne Boland, Marie-Noelle Bonnet-Dupeyron, Elise Brischoux-Boucher, Céline Bonnet, Marie Bournez, Odile Boute, Perrine Brunelle, Roseline Caumes, Perrine Charles, Nicolas Chassaing, Nicolas Chatron, Benjamin Cogné, Estelle Colin, Valérie Cormier-Daire, Rodolphe Dard, Benjamin Dauriat, Julian Delanne, Jean-François Deleuze, Florence Demurger, Anne-Sophie Denommé-Pichon, Christel Depienne, Anne Dieux Coeslier, Christèle Dubourg, Patrick Edery, salima EL CHEHADEH, Laurence Faivre, Mélanie FRADIN, Aurore Garde, David Geneviève, Brigitte Gilbert-Dussardier, Cyril Goizet, Alice Goldenberg, Evan Gouy, Anne-Marie Guerrot, Anne Guimier, Ines HARZALLAH, Delphine Héron, Bertrand Isidor, Xavier Le Guillou Horn, Boris Keren, Alma Kuechler, Elodie Lacaze, Alinoë Lavillaureix, Daphné Lehalle, Gaetan Lesca, James Lespinasse, Jonathan Levy, Stanislas Lyonnet, Godelieve Morel, Nolwenn Jean Marçais, Sandrine Marlin, Luisa Marsili, Cyril Mignot, Sophie Nambot, Mathilde Nizon, Robert Olaso, Laurent PASQUIER, Laurine Perrin, Florence Petit, Amélie Piton, Fabienne Prieur, Audrey Putoux, Marc Planes, Sylvie Odent, Chloé Quelin, Sylvia Quemener, Mélanie Rama, Marlène RIO, Massimiliano Rossi, Elise Schaefer, Sophie Rondeau, Pascale SAUGIER-VEBER, Thomas Smol, Sabine Sigaudy, Renaud TOURAINE, Frédéric Tran-Mau-Them, Aurélien Trimouille, Clémence Vanlerberghe, Valérie Vantalon, Gabriella Vera, Marie Vincent, Alban Ziegler, Olivier Guillin, Dominique Campion, and Camille Charbonnier

Abstract

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 102 carriers of (likely) pathogenic variants in ten different genes, 58 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached less than 40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70%-100% sensibility at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.

Published
2023

19. Lessons from two series by physicians and caregivers’ self-reported data, and DNA methylation profile in DDX3X-Related Disorders

Author

David Geneviève, Valentin Ruault, Pauline Burger, Johanna Gradels-Hauguel, Nathalie Ruiz-Pallares, Xtraordinaire Association, Rami Abou Jamra, Alexandra Afenjar, Yves Alembik, Jean-Luc Alessandri, Arpin Stéphanie, Giulia Barcia, Šárka Bendová, Ange-Line Bruel, Perrine Charles, Nicolas Chatron, Maya Chopra, Solène Conrad, Valérie Cormier-Daire, Auriane Cospain, Christine Coubes, Juliette Coursimault, Andrée Delahaye-Duriez, Martine Doco-Fenzy, William Dufour, Benjamin Durand, Camille ENGEL, Laurence Faivre, Fanny Ferroul, Mélanie FRADIN, Hélène Frenkiel, Carlo Fusco, Livia Garavelli, Aurore Garde, Bénédicte Gérard, David Germanaud, Louise Goujon, Aurélie Gouronc, Emmanuelle Ginglinger, Alice Goldenberg, Miroslava Hancarova, Delphine Héron, Bertrand Isidor, Nolwenn Jean Marçais, Boris Keren, Margarete Koch-Hogrebe, Paul Kuentz, Victoria Lamure, Anne-Sophie Lebre, François Lecoquierre, Natacha Lehman, Gaetan Lesca, Stanislas Lyonnet, Delphine Martin, Cyril Mignot, Teresa Neuhann, Gaël Nicolas, Mathilde Nizon, Florence Petit, Christophe Philippe, Amélie Piton, Marzia Pollazzon, Darina Prchalova, Audrey Putoux, Marlène RIO, Sophie Rondeau, Massimiliano Rossi, Quentin Sabbagh, Pascale Saugier-Veber, Ariane Schmetz, Julie Steffann, Christel Thauvin-Robinet, Annick Toutain, Frédéric Tran-Mau-Them, Gabriele Trimarchi, Marie Vincent, Marketa Vlckova, Dagmar Wieczorek, Marjolaine Willems, kevin yauy, Michaela Zelinová, Alban Ziegler, Boris Chaumette, Bekim Sadikovic, and Jean-Louis Mandel

Abstract

We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.

Published
2023

20. Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel–Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study

Author

Marc Bardou, Pierre Vabres, Laurence Faivre, Annabel Maruani, Victoria E R Parker, A. Phan, Christine Chiaverini, L. Martin, Jill Clayton-Smith, C. Fleck, Maxime Luu, Tristan Mirault, Fanny Morice-Picard, M. Carpentier, Marie-Line Jacquemont, Hervé Devilliers, Marjolaine Willems, A. Maurer, Romaric Loffroy, Didier Bessis, Florence Petit, Robert K. Semple, M. Yousfi, 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Référence des Maladies Génétiques à Expression Cutanée (MAGEC), Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institute of Applied Physics [Bern] (IAP), University of Bern, CHU Bordeaux [Bordeaux], Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire de Lille (CHU de Lille), Hôpital Lapeyronie [Montpellier] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre national de référence des maladies vasculaires rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Manchester [Manchester], CHU Dijon, AstraZeneca [Cambridge, UK], University of Edinburgh, 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 Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, and 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

Subjects
Adult, Klippel-Trenaunay-Weber Syndrome, medicine.medical_specialty, Klippel-Trenaunay syndrome, Syzygium, [SDV]Life Sciences [q-bio], Population, Overgrowth syndrome, Article, Phosphatidylinositol 3-Kinases, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Internal medicine, taselisib, medicine, Humans, education, Adverse effect, Genetics (clinical), education.field_of_study, business.industry, Imidazoles, clinical trial, PIK3CA, medicine.disease, 3. Good health, Clinical trial, Oxazepines, Tolerability, 030220 oncology & carcinogenesis, Mutation, Cohort, Quality of Life, mosaic, business, PROS treatment
Abstract

International audience; ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort ( n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Published
2021

21. GnRH regulates the expression of its receptor accessory protein SET in pituitary gonadotropes.

Author

Charlotte Avet, Chantal Denoyelle, David L'Hôte, Florence Petit, Céline J Guigon, Joëlle Cohen-Tannoudji, and Violaine Simon

Subjects
Medicine, Science
Abstract

Reproductive function is under the control of the neurohormone GnRH, which activates a G-protein-coupled receptor (GnRHR) expressed in pituitary gonadotrope cells. GnRHR activates a complex signaling network to regulate synthesis and secretion of the two gonadotropin hormones, luteinizing hormone and follicle-stimulating hormone, both regulating gametogenesis and steroidogenesis in gonads. Recently, in an attempt to identify the mechanisms underlying GnRHR signaling plasticity, we identified the first interacting partner of GnRHR, the proto-oncogene SET. We showed that SET binds to intracellular domains of GnRHR to enhance its coupling to cAMP pathway in αT3-1 gonadotrope cells. Here, we demonstrate that SET protein is rapidly regulated by GnRH, which increases SET phosphorylation state and decreases dose-dependently SET protein level. Our results highlight a post-translational regulation of SET protein involving the proteasome pathway. We determined that SET phosphorylation upon GnRH stimulation is mediated by PKC and that PKC mediates GnRH-induced SET down-regulation. Phosphorylation on serine 9 targets SET for degradation into the proteasome. Furthermore, a non-phosphorylatable SET mutant on serine 9 is resistant to GnRH-induced down-regulation. Altogether, these data suggest that GnRH-induced SET phosphorylation on serine 9 mediates SET protein down-regulation through the proteasome pathway. Noteworthy, SET down-regulation was also observed in response to pulsatile GnRH stimulation in LβT2 gonadotrope cells as well as in vivo in prepubertal female mice supporting its physiological relevance. In conclusion, this study highlights a regulation of SET protein by the neurohormone GnRH and identifies some of the mechanisms involved.

Published
2018
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22. Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

Author

Andy Nguyen, Endika Haro, Florence Petit, Lauren I. Yorozuya, Kerby C. Oberg, Anne-Sophie Jourdain, Florence Fellmann, Conor D. Spady, Marian A. Ros, Sylvie Manouvrier-Hanu, Charmaine U. Pira, Christine Francannet, Jean-Marc Good, Sara Lucas-Toca, Fabienne Escande, Austin L. Gray, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), and Rare Disorders Consortium Disease Network (US)

Subjects
Male, Science, LIM-Homeodomain Proteins, General Physics and Astronomy, Biology, Development, Bioinformatics, Article, General Biochemistry, Genetics and Molecular Biology, Mesoderm, Mice, Genes, Reporter, Nail-Patella Syndrome, medicine, Animals, Humans, Autoregulation, Enhancer, Gene, Nail patella syndrome, Kidney, Multidisciplinary, Base Sequence, Disease genetics, Disease model, Homozygote, Extremities, General Chemistry, medicine.disease, Phenotype, Chromatin, Pedigree, medicine.anatomical_structure, Organ Specificity, Female, Haploinsufficiency, Chickens, Gene Deletion, Transcription Factors, Kidney disease
Abstract

© The Author(s) 2021., LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis., This work was supported in part by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (M.A.R) (BFU2017-88265-P); the National Organization for Rare Disorders (K.C.O.), and the Loma Linda University Pathology Research Endowment Fund (K.C.O.).

Published
2021

23. AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

Author

Julie Leclerc, Marie Beaumont, Roseline Vibert, Stéphane Pinson, Catherine Vermaut, Cathy Flament, Tonio Lovecchio, Lucie Delattre, Christophe Demay, Florence Coulet, Erell Guillerm, Nadim Hamzaoui, Patrick R. Benusiglio, Afane Brahimi, François Cornelis, Hélène Delhomelle, Sandra Fert‐Ferrer, Benjamin P. J. Fournier, Alain Hovnanian, Clémentine Legrand, Alain Lortholary, David Malka, Florence Petit, Jean‐Christophe Saurin, Sophie Lejeune, Chrystelle Colas, Marie‐Pierre Buisine, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie orale moléculaire = Molecular Oral Pathophysiology [CRC], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-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)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Wnt signaling pathway, Cancer Research, colorectal cancer susceptibility, [SDV]Life Sciences [q-bio], Genetics, oligodontia, adenomatous polyposis
Abstract

International audience; Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss‐of‐function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103–28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3‐binding and DIX domains, but preserving the β‐catenin‐binding domain. Ninety‐one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.

Published
2022

24. S62798, a potent TAFIa inhibitor, accelerates endogenous fibrinolysis in a murine model of pulmonary thromboembolism

Author

Isabelle Lapret, Philippe Delerive, Florence Petit-Dop, Paul Declerck, Isabelle Tupinon-Mathieu, Patricia Sansilvestri-Morel, Philippe Baumy, Marie-Odile Vallez, Alain Rupin, Florence Bertin, Schaffner Arnaud-Pierre, and Philippe Mennecier

Subjects
Carboxypeptidase B2, medicine.medical_treatment, 030204 cardiovascular system & hematology, Pharmacology, Fibrin, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Fibrinolysis, medicine, Animals, Humans, Enzyme Inhibitors, biology, business.industry, Hematology, Heparin, Thrombolysis, medicine.disease, Rats, Pulmonary embolism, Disease Models, Animal, Thromboelastometry, Venous thrombosis, 030220 oncology & carcinogenesis, biology.protein, Fibrin Clot Lysis Time, Pulmonary Embolism, business, medicine.drug
Abstract

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified. Its ability to enhance fibrinolysis was investigated both in vitro and in vivo in a mouse model of pulmonary thromboembolism, as well as its effect on bleeding. S62798 is a highly selective human, mouse and rat TAFIa inhibitor (IC50 = 11; 270; 178 nmol/L, respectively). It accelerates lysis of a human clot in vitro, evaluated by thromboelastometry (EC50 = 27 nmol/L). In a rat tail bleeding model, no effect of S62798 treatment was observed up to 20 mg/kg. Enhancement of endogenous fibrinolysis by S62798 was investigated in a mouse model of Tissue Factor-induced pulmonary thromboembolism. Intravenous administration of S62798 decreased pulmonary fibrin clots with a minimal effective dose of 0.03 mg/kg. Finally, effect of S62798 in combination with heparin was evaluated. When treatment of heparin was done in a curative setting, no effect was observed whereas a significantly decreased pulmonary fibrin deposition was observed in response to S62798 alone or in combination with heparin. This study demonstrates that S62798 is a potent TAFIa inhibitor with minimal risk of bleeding. In vivo, curative S62798 intravenous treatment, alone or associated with heparin, accelerated clot lysis by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin clots. S62798 is expected to be a therapeutic option for pulmonary embolism patients on top of anticoagulants.

Published
2021

25. Clinical and neuroimaging findings in 33 patients with <scp>MCAP</scp> syndrome: A survey to evaluate relevant endpoints for future clinical trials

Author

Florence Petit, Fabienne Giuliano, Juliette Mazereeuw-Hautier, Marjolaine Willems, Christel Thauvin-Robinet, Patricia Blanchet, Laurence Faivre, Elodie Gautier, Anne-Claire Bursztejn, Renaud Touraine, Annick Toutain, Frederico Di Rocco, Maxime Luu, Patrick Edery, Arthur Sorlin, Jean-Luc Alessandri, Nicolas Chassaing, Alice Goldenberg, Christine Chiaverini, Fanny Morice-Picard, Aurore Garde, Stéphanie Arpin, Massimiliano Rossi, Marc Bardou, Claire Nicolas, Gilles Morin, Jenny Cornaton, Cyril Mignot, Christophe Philippe, V. Carmignac, Rodolphe Dard, Joelle Roume, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Pierre Vabres, Didier Lacombe, Diane Doummar, Lucile Pinson, Christine Coubes, Laurent Guibaud, Olivia Boccara, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cutis marmorata, Adolescent, Class I Phosphatidylinositol 3-Kinases, Neuroimaging, Context (language use), Skin Diseases, Vascular, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Genetics, Polymicrogyria, medicine, Humans, PROS, Abnormalities, Multiple, Telangiectasis, Megalencephaly, Child, MCAP syndrome, Genetics (clinical), Chiari malformation, Clinical Trials as Topic, business.industry, Macrocephaly, PIK3CA, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Clinical trial, 030104 developmental biology, Child, Preschool, Postnatal macrocephaly, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Forecasting, Ventriculomegaly
Abstract

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Published
2021

26. Le test de concordance de script à l’heure de la réforme du second cycle des études médicales en France : étude pilote en génétique médicale

Author

Louis Sibert, Alexandre Louvet, Sabrina Guyart, Jamal Ghoumid, Jerome Sige, Florence Petit, Thomas Smol, Dominique Lacroix, Simon Boussion, Perrine Brunelle, Sylvie Manouvrier, and Didier Gosset

Subjects
03 medical and health sciences, 0302 clinical medicine, 020205 medical informatics, 0202 electrical engineering, electronic engineering, information engineering, 030212 general & internal medicine, 02 engineering and technology
Abstract

Contexte : Dans les prochaines années, il est prévu d’introduire le test de concordance de script (TCS) dans le cadre des épreuves classantes nationales informatisées (ECNi). Le TCS n’a jamais été évalué pour l’enseignement de la génétique médicale du deuxième cycle. But : Élaborer un TCS pour les étudiants de deuxième cycle et évaluer ses qualités psychométriques. Déterminer les arguments docimologiques étayant la pertinence d’introduire le TCS aux ECNi. Méthode : Création d’un TCS spécifique à la discipline et administration aux étudiants de deuxième cycle et internes de génétique médicale. Administration d’une épreuve type ECNi comportant 3 dossiers progressifs (DP) et 12 questions isolées (QI) aux étudiants de deuxième cycle. Analyse du caractère discriminant du TCS par comparaison des scores obtenus par les différents groupes. Analyse de corrélation entre les scores aux TCS et DP, QI et rang de classement aux ECNi. Résultats : Les réponses de 18 experts et 129 étudiants ont été obtenues. Après optimisation, le TCS contient 15 vignettes cliniques et 34 items. Le coefficient alpha de Cronbach est de 0,67. Le test a pu discriminer le niveau des étudiants et il existe une corrélation entre les scores obtenus au TCS, aux DP, ainsi qu’avec le rang de classement aux ECNi. Conclusion : Cette étude montre la faisabilité d’un TCS standardisé pour évaluer l’enseignement de la génétique médicale, qui pourrait être aisément intégré aux ECNi. Il s’agit d’un exemple supplémentaire de la pertinence de ce type d’épreuve dans l’évaluation du raisonnement clinique des étudiants de médecine.

Published
2021

27. MO047: Biallelic pathogenic variants in ROBO1 associate with syndromic CAKUT

Author

Johannes Münch, Marie Engesser, Ria Schönauer, J Austin Hamm, Gulsen Akay, Beyhan Tüysüz, Toshihiko Shirakawa, Sumito Dateki, Laura Claus, Albertien M van Eerde, Timo Wagner, Carsten Bergmann, Jillian Buchan, Tara Wegner, Jennifer Posey, James R Lupski, Florence Petit, Andrew A Mccarthy, Gregory J Pazour, Cecilia W Lo, Bernt Popp, and Jan Halbritter

Subjects
Transplantation, Nephrology
Abstract

BACKGROUND AND AIMS Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. METHOD We collected phenotypic data of all participants. Genetic analysis was conducted by either exome or whole genome sequencing, respectively. We used Sanger sequencing for variant confirmation and segregation analysis and performed in-silico analysis of identified missense variants. In an ENU-induced mouse model, we examined mice with the mutation Robo1Ile270Thr/Ile270Thr. RESULTS By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses from Germany, France, Turkey, Japan and the USA with biallelic truncating or combined missense and truncating variants in ROBO1. Renal and genitourinary manifestation included unilateral or bilateral renal agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation and increased renal echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects (Figure 1). By in-silico analysis, we determined the functional significance of identified missense variants and observed absence of renal ROBO1 expression in both human and murine mutant tissues (Figure 2). CONCLUSION This study describes six live-born and two non-viable individuals with syndromic CAKUT due to probably deleterious ROBO1 variants. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. In conclusion, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Conversely, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for renal involvement is indicated.

Published
2022

28. Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases

Author

Nancy Vegas, Zeynep Demir, Christopher T. Gordon, Sylvain Breton, Vanessa L. Romanelli Tavares, Hugo Moisset, Roseli Zechi‐Ceide, Nancy M. Kokitsu‐Nakata, Yasuhiro Kido, Sandrine Marlin, Souad Gherbi Halem, Ilse Meerschaut, Bert Callewaert, Brian Chung, Nicole Revencu, Daphné Lehalle, Florence Petit, Evan J. Propst, Blake C. Papsin, John H. Phillips, Linda Jakobsen, Pauline Le Tanno, Julien Thévenon, Julie McGaughran, Erica H. Gerkes, Chiara Leoni, Peter Kroisel, Tiong Y. Tan, Alex Henderson, Paulien Terhal, Lina Basel‐Salmon, Adila Alkindy, Susan M. White, Maria R. Passos‐Bueno, Véronique Pingault, Loïc De Pontual, Jeanne Amiel, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de malformations vasculaires congénitales, and UCL - (SLuc) Centre de génétique médicale UCL

Subjects
GNAI3, craniofacial anomalies, NEURAL CREST, CONDYLAR SYNDROME, MUTATIONS, Ear, PLCB4, QUESTION MARK EAR, TRANSFORMATION, Pedigree, MECHANISMS, GENÉTICA, INSIGHTS, Phenotype, Medicine and Health Sciences, Genetics, Humans, EDN1, Ear Diseases, auriculocondylar syndrome, MEF2C, Genetics (clinical)
Abstract

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a “Question Mark Ear” (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Published
2022

29. TRIT1 deficiency: Two novel patients with four novel variants

Author

Thomas Smol, Perrine Brunelle, Roseline Caumes, Odile Boute-Benejean, Caroline Thuillier, Martin Figeac, Emilie Ait-Yahya, Fabrice Bonte, Frederic Tran Mau-Them, Christel Thauvin-Robinet, Laurence Faivre, Catherine Roche-Lestienne, Sylvie Manouvrier-Hanu, Florence Petit, and Jamal Ghoumid

Subjects
Alkyl and Aryl Transferases, Phenotype, RNA, Transfer, Genetics, Microcephaly, Humans, General Medicine, Codon, Genetics (clinical), Alleles, Mitochondria
Abstract

TRIT1 encodes a tRNA isopentenyl transferase that allows a strong interaction between the mini helix and the codon. Recent reports support the TRIT1 bi-allelic alterations as the cause of an autosomal recessive disorder, named combined oxydative phophorylation deficiency 35, with microcephaly, developmental disability, and epilepsy. The phenotype is due to decreased mitochondrial function, with deficit of i6A37 in cytosolic and mitochondrial tRNA. Only 10 patients have been reported. We report on two new patients with four novel variants, and confirm the published clinical TRIT1 deficient phenotype stressing the possibility of both very severe, with generalized pharmaco-resistant seizures, and mild phenotypes.

Published
2022

30. Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study

Author

Guillaume Jouret, Solveig Heide, Arthur Sorlin, Laurence Faivre, Sandra Chantot‐Bastaraud, Claire Beneteau, Marie Denis‐Musquer, Peter D. Turnpenny, Charles Coutton, Gaëlle Vieville, Julien Thevenon, Austin Larson, Florence Petit, Elise Boudry, Thomas Smol, Bruno Delobel, Bénédicte Duban‐Bedu, Chiara Fallerini, Francesca Mari, Caterina Lo Rizzo, Alessandra Renieri, Jean‐Hubert Caberg, Anne‐Sophie Denommé‐Pichon, Frédéric Tran Mau‐Them, Isabelle Maystadt, Thomas Courtin, Boris Keren, Linda Mouthon, Perrine Charles, Silvestre Cuinat, Bertrand Isidor, Philippe Theis, Christian Müller, Marizela Kulisic, Seval Türkmen, Daniel Stieber, Dominique Bourgeois, Emmanuel Scalais, Barbara Klink, Couvet, Sandrine, Laboratoire National de Santé [Luxembourg] (LNS), 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), 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), 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), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Laboratoire de Génétique Chromosomique [CHU de Grenoble], CHU Grenoble, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Siena = University of Siena (UNISI), Azienda Ospedaliera Universitaria Senese, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre de Génétique Humaine [Charleroi, Belgium] (Institut de Pathologie et de Génétique), Institut de Pathologie et de Génétique, Charleroi, Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Centre Hospitalier de Luxembourg [Luxembourg] (CHL)

Subjects
MESH: Mutation, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, NIPBL, BRD4-related syndrome, cohesinopathy, MESH: Cell Cycle Proteins, MESH: Pregnancy, Pregnancy, MESH: Child, De Lange Syndrome, Genetics, Humans, Child, Genetics (clinical), MESH: Humans, MESH: Genomics, Nuclear Proteins, MESH: Transcription Factors, Genomics, Cornelia de Lange syndrome, [SDV] Life Sciences [q-bio], Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, BRD4, Female, MESH: Female, MESH: Nuclear Proteins, MESH: De Lange Syndrome, Transcription Factors
Abstract

International audience; BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.

Published
2022

31. De novo missense variants in the <scp> RAP1B </scp> gene identified in two patients with syndromic thrombocytopenia

Author

Anna Raimbault, Susanne Morlot, Chen Du, Tim Ripperger, Gunnar Schmidt, Thomas Smol, Winfried Hofmann, Bernd Auber, Doris Steinemann, Gudrun Göhring, Anne Lambilliotte, Brigitte Schlegelberger, Emilie Ait-Yahya, Florence Petit, Jan Hendrik Niemann, and Beate Kaune

Subjects
Adult, Male, 0301 basic medicine, Heterozygote, Microcephaly, Adolescent, Mutation, Missense, 030105 genetics & heredity, Biology, Germline, 03 medical and health sciences, Intellectual Disability, Exome Sequencing, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Exome, MULTIPLE MALFORMATIONS, Child, Genetics (clinical), Exome sequencing, medicine.disease, RAP1B gene, Thrombocytopenia, Pancytopenia, Pedigree, Phenotype, rap GTP-Binding Proteins, 030104 developmental biology, Child, Preschool, Female, Kabuki syndrome
Abstract

We present two independent cases of syndromic thrombocytopenia with multiple malformations, microcephaly, learning difficulties, dysmorphism and other features. Exome sequencing identified two novel de novo heterozygous variants in these patients, c.35G>T p.(Gly12Val) and c.178G>C p.(Gly60Arg), in the RAP1B gene (NM_001010942.2). These variants have not been described previously as germline variants, however functional studies in literature strongly suggest a clinical implication of these two activating hot spot positions. We hypothesize that pathogenic missense variants in the RAP1B gene cause congenital syndromic thrombocytopenia with a spectrum of associated malformations and dysmorphism, possibly through a gain of function mechanism.

Published
2020

32. ERα orchestre les mécanismes épigénétiques qui déclenchent l’expression du gène Sf-1 au cours de la différenciation du lignage gonadotrope hypophysaire

Author

David L'Hôte, Vincent Pacini, Bruno Querat, Florence Petit, Joëlle Cohen-Tannoudji, Jean-Noël Laverrière, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Regulation of gene expression, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, General Medicine, Biology, Molecular biology, ComputingMilieux_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology, Epigenesis
Abstract

International audience

Published
2020

33. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author

Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract

Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Published
2020

34. Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Author

Johannes Münch, Marie Engesser, Ria Schönauer, J. Austin Hamm, Christin Hartig, Elena Hantmann, Gulsen Akay, Davut Pehlivan, Tadahiro Mitani, Zeynep Coban Akdemir, Beyhan Tüysüz, Toshihiko Shirakawa, Sumito Dateki, Laura R. Claus, Albertien M. van Eerde, Thomas Smol, Louise Devisme, Hélène Franquet, Tania Attié-Bitach, Timo Wagner, Carsten Bergmann, Anne Kathrin Höhn, Shirlee Shril, Ari Pollack, Tara Wenger, Abbey A. Scott, Sarah Paolucci, Jillian Buchan, George C. Gabriel, Jennifer E. Posey, James R. Lupski, Florence Petit, Andrew A. McCarthy, Gregory J. Pazour, Cecilia W. Lo, Bernt Popp, and Jan Halbritter

Subjects
Male, Vesico-Ureteral Reflux, Nerve Tissue Proteins, Kidney, Article, Mice, Nephrology, Urogenital Abnormalities, Animals, Humans, Female, Receptors, Immunologic, Child, Urinary Tract
Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.

Published
2022

35. Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Author

Mary R. Sy, Jaynee Chauhan, Katrina Prescott, Aliza Imam, Alison Kraus, Ana Beleza, Lee Salkeld, Saraswati Hosdurga, Michael Parker, Pradeep Vasudevan, Lily Islam, Himanshu Goel, Nicole Bain, Soo‐Mi Park, Shehla Mohammed, Klaus Dieterich, Charles Coutton, Véronique Satre, Gaëlle Vieville, Alan Donaldson, Claire Beneteau, Jamal Ghoumid, Kris Van Den Bogaert, Anneleen Boogaerts, Elise Boudry, Clémence Vanlerberghe, Florence Petit, Laura Bernardini, Barbara Torres, Teresa Mattina, Diana Carli, Giorgia Mandrile, Michele Pinelli, Nicola Brunetti‐Pierri, Katherine Neas, Rachel Beddow, Pernille M. Tørring, Flavio Faletra, Beatrice Spedicati, Paolo Gasparini, Alessandro Mussa, Giovanni Battista Ferrero, Anne Lampe, Wayne Lam, Weimin Bi, Carlos A. Bacino, Akela Kuwahara, Jeffrey O. Bush, Xiaonan Zhao, Pamela N. Luna, Chad A. Shaw, Jill A. Rosenfeld, Daryl A. Scott, Sy, Mary R, Chauhan, Jaynee, Prescott, Katrina, Imam, Aliza, Kraus, Alison, Beleza, Ana, Salkeld, Lee, Hosdurga, Saraswati, Parker, Michael, Vasudevan, Pradeep, Islam, Lily, Goel, Himanshu, Bain, Nicole, Park, Soo-Mi, Mohammed, Shehla, Dieterich, Klau, Coutton, Charle, Satre, Véronique, Vieville, Gaëlle, Donaldson, Alan, Beneteau, Claire, Ghoumid, Jamal, Van Den Bogaert, Kri, Boogaerts, Anneleen, Boudry, Elise, Vanlerberghe, Clémence, Petit, Florence, Bernardini, Laura, Torres, Barbara, Mattina, Teresa, Carli, Diana, Mandrile, Giorgia, Pinelli, Michele, Brunetti-Pierri, Nicola, Neas, Katherine, Beddow, Rachel, Tørring, Pernille M, Faletra, Flavio, Spedicati, Beatrice, Gasparini, Paolo, Mussa, Alessandro, Ferrero, Giovanni Battista, Lampe, Anne, Lam, Wayne, Bi, Weimin, Bacino, Carlos A, Kuwahara, Akela, Bush, Jeffrey O, Zhao, Xiaonan, Luna, Pamela N, Shaw, Chad A, Rosenfeld, Jill A, and Scott, Daryl A

Subjects
tracheoesophageal fistula, NRXN1, Fanconi anemia, Genetics, Humans, TCF4, esophageal atresia, exome sequencing, Exome, Genetics (clinical)
Abstract

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Published
2022

36. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author

Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta

Subjects
musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Published
2022

37. Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα-dependent mechanism

Author

Alice Pierre, Celine J. Guigon, Catherine Genestie, Sung Hoon Kim, Florence Petit, Marie M Devillers, Victoria Cluzet, Anne Mayeur, David L'Hôte, Eloise Airaud, John A. Katzenellenbogen, Isabelle Treilleux, Frank Giton, Joëlle Cohen-Tannoudji, Stéphanie Chauvin, Alexandra Leary, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Léon Bérard [Lyon], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)

Subjects
Cell Survival, ANTI-MULLERIAN HORMONE, [SDV]Life Sciences [q-bio], Granulosa cell, Estrogen receptor, Biology, ESTROGEN-RECEPTOR-BETA, THERAPY, Pathology and Forensic Medicine, Receptors, G-Protein-Coupled, Ovarian tumor, Cell Line, Tumor, medicine, Estrogen Receptor beta, Humans, Receptor, GENE-EXPRESSION, Aged, Cell Proliferation, Granulosa Cell Tumor, Ovarian Neoplasms, Estradiol, Estrogen Receptor alpha, Middle Aged, medicine.disease, Neoplasm Proteins, Up-Regulation, GREB1, Gene Expression Regulation, Neoplastic, INHIBIN, Receptors, Estrogen, MARKER, Cancer research, LIGANDS, Female, Ovarian cancer, GPER, Estrogen receptor alpha, Signal Transduction
Abstract

International audience; Granulosa cell tumor (GCT) is a form of ovarian tumor characterized by its tendency to recur years after surgical ablation. Little is known about the mechanisms involved in GCT development and progression. GCTs can produce estradiol (E2), but whether this hormone could play a role in this cancer through its nuclear receptors, i.e. ER alpha and ER beta, remains unknown. Here, we addressed this issue by cell-based and molecular studies on human GCTs and GCT cell lines. Importantly, we observed that E2 significantly increased the growth of GCT cells by promoting cell survival. The use of selective agonists of each type of receptor, together with Esr1 (ER alpha) or Esr2 (ER beta)-deleted GCT cells, revealed that E2 mediated its effects through ER alpha-dependent genomic mechanisms and ER beta/ER alpha-dependent extra-nuclear mechanisms. Notably, the expression of Greb1, a prototypical ER target gene, was dose-dependently upregulated by E2 specifically through ER alpha in GCT cells. Accordingly, using GCTs from patients, we found that GREB1 mRNA abundance was positively correlated to intra-tumoral E2 concentrations. Tissue microarray analyses showed that there were various combinations of ER expression in primary and recurrent GCTs, and that ER alpha expression persisted only in combination with ER beta in similar to 40% of recurrent tumors. Altogether, this study demonstrates that E2 can promote the progression of GCTs, with a clear dependence on ER alpha. In addition to demonstrating that GCTs can be classified as a hormone-related cancer, our results also highlight that the nature of ER forms present in recurrent GCTs could underlie the variable efficiency of endocrine therapies. (C) 2022 The Pathological Society of Great Britain and Ireland.

Published
2021

38. Neurons expressing mu opioid receptors of the habenula promote negative affect in a projection-specific manner

Author

Julie Bailly, Chloé Tirel, Emmanuel Darcq, Florence Petit, Florence Allain, and Brigitte L. Kieffer

Subjects
Elevated plus maze, Interpeduncular nucleus, Optogenetics, Biology, Open field, Marble burying, Habenula, Dorsal raphe nucleus, medicine.anatomical_structure, nervous system, mental disorders, medicine, Neuron, Neuroscience
Abstract

BACKGROUNDThe mu opioid receptor (MOR) is central to hedonic balance, and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, and notably the medial habenula (MHb) where the receptor is highly dense, however this was not investigated. Our prior data suggest that the inhibitory activity of MOR in the MHb limits aversive states. Here we therefore tested the hypothesis that neurons expressing MOR in the MHb (MHb-MOR neurons) promote negative affective states.METHODSUsing Oprm1-Cre knock-in mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of MHb-MOR neuron stimulation in approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze and marble burying) and despair-like behavior (tail suspension).RESULTSOpto-stimulation of MHb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus (IPN), MHb-MOR neurons project to the dorsal raphe nucleus (DRN), uncovering a yet unreported connection of MHb to a main mood center. Opto-stimulation of MHb-MOR/IPN neurons triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of MHb-MOR/DRN neurons increased levels of anxiety with no effect on other behaviors, revealing two dissociable pathways controlling negative affect.CONCLUSIONSThis study demonstrates aversive activity of MHb neurons that respond to MOR opioids. We propose that inhibition of these neurons by endogenous or exogenous opioids relieves negative affect via two distinct MHb microcircuits, contributing to despair-like behavior (MHb-MOR/IPN) and anxiety (MHb-MOR/DRN). This mechanism has implications for hedonic homeostasis and addiction.

Published
2021

39. Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects

Author

Hernandez P, Gilbert-Dussardier B, Boris Keren, Ai X, Eric L. Bogenschutz, J. Wells, Zeynep Coban-Akdemir, Julia Wynn, Frédéric Frénois, Contreras Htm, Lupski, Andres Hernandez-Garcia, Ropers Hh, Lu Qiao, Florence Petit, Yonath H, Richard S. Maser, Anne-Sophie Jourdain, Delrue M, Giampietro Pf, Clark Rd, Wendy K. Chung, Harrison Brand, McCulley D, Tiana M. Scott, Mauro Longoni, Bult Cj, Patricia K. Donahoe, Barbara R. Pober, Frances A. High, Rebecca Hernan, Maria Loscertales, Yufeng Shen, Daryl A. Scott, Devisme L, Dysart Mj, Daniel G. Calame, and Hu H

Subjects
Genetics, Stress fiber, PLS3, medicine, Missense mutation, Congenital diaphragmatic hernia, Biology, medicine.disease, Actin cytoskeleton, Phenotype, Exome, Actin
Abstract

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with a novel X-linked condition characterized by diaphragm defects, variable anterior body wall anomalies, and/or facial dysmorphism. Using linkage analysis and whole exome or whole genome sequencing, we identified novel missense variants in the actin binding domains of plastin 3 (PLS3), a gene encoding an actin bundling protein, that co-segregate with disease in all families. Loss-of-function variants in PLS3 have been described previously in association with X-linked osteoporosis. To address these seemingly disparate clinical phenotypes, we performed in silico protein modeling and cellular overexpression experiments, which suggest that the affected residues in individuals with CDH are important for actin binding and result in disorganization of the actin cytoskeleton and a reduction in normal actin stress fiber formation. A mouse knock-in model of a variant identified in one of the families, p.W499C, shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal wall defects. Both the mouse model and one surviving adult patient with a PLS3 variant were observed to have increased, rather than decreased, bone mineral density. Together, these clinical and functional data in human and mouse reveal that specific missense variants affecting the actin binding domains of PLS3 may have a gain-of-function effect and cause a new Mendelian disorder.

Published
2021

40. Performance of meta-predictors for the classification of MED13L missense variations, implication of raw parameters

Author

Sylvie Manouvrier-Hanu, Jamal Ghoumid, Frédéric Frénois, Thomas Smol, and Florence Petit

Subjects
Phosphorylation sites, Mediator Complex, Individual gene, Mutation, Missense, General Medicine, Computational biology, Biology, medicine.disease, Hypotonia, DNA sequencing, Intellectual disability, Genetics, medicine, Missense mutation, Humans, In patient, medicine.symptom, Exome, Genetics (clinical), Algorithms
Abstract

MED13L syndrome is a rare congenital disorder comprising moderate intellectual disability, hypotonia and facial dysmorphism. Whole exome or genome sequencing in patients with non-specific neurodevelopmental disorders leads to identification of an increasing number of MED13L missense variations of unknown signification. The aim of our study was to identify relevant annotation parameters enhancing discrimination between candidate pathogenic or neutral missense variations, and to assess the performance of seven meta-predictor algorithms: BayesDel, CADD, DANN, FATHMM-XF, M-CAP, MISTIC and REVEL for the classification of MED13L missense variants. Significant differences were identified for five parameters: global conservation through verPhyloP and verPhCons scores; physico-chemical difference between amino acids estimated by Grantham scores; conservation of residues between MED13L and MED13 protein; proximity to phosphorylation sites for pathogenic variations. Among the seven selected in-silico tools, BayesDel, REVEL, and MISTIC provided the most interesting performances to discriminate pathogenic from neutral missense variations. Individual gene parameter studies with MED13L have provided expertise on elements of annotation improving meta-predictor choices. The in-silico approach allows us to make valuable hypotheses to predict the involvement of these amino acids in MED13L pathogenic missense variations.

Published
2021

41. Severe phenotype in patients with large deletions of NF1

Author

Laurence, Pacot, Dominique, Vidaud, Audrey, Sabbagh, Ingrid, Laurendeau, Audrey, Briand-Suleau, Audrey, Coustier, Théodora, Maillard, Cécile, Barbance, Fanny, Morice-Picard, Sabine, Sigaudy, Olga O, Glazunova, Lena, Damaj, Valérie, Layet, Chloé, Quelin, Brigitte, Gilbert-Dussardier, Frédérique, Audic, Hélène, Dollfus, Anne-Marie, Guerrot, James, Lespinasse, Sophie, Julia, Marie-Christine, Vantyghem, Magali, Drouard, Marilyn, Lackmy, Bruno, Leheup, Yves, Alembik, Alexia, Lemaire, Patrick, Nitschké, Florence, Petit, Anne, Dieux Coeslier, Eugénie, Mutez, Alain, Taieb, Mélanie, Fradin, Yline, Capri, Hala, Nasser, Lyse, Ruaud, Benjamin, Dauriat, Sylvie, Bourthoumieu, David, Geneviève, Séverine, Audebert-Bellanger, Mathilde, Nizon, Radka, Stoeva, Geoffroy, Hickman, Gaël, Nicolas, Juliette, Mazereeuw-Hautier, Arnaud, Jannic, Salah, Ferkal, Béatrice, Parfait, Michel, Vidaud, Members Of The Nf France Network, Pierre, Wolkenstein, Eric, Pasmant, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cancer Research and Personalized Medicine - CARPEM [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-CHU Necker - Enfants Malades [AP-HP], GHU AP-HP Centre Université de Paris, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pontchaillou [Rennes], Groupe Hospitalier du Havre, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hôpital Sud [CHU Rennes], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Métropole Savoie [Chambéry], CHU Toulouse [Toulouse], Hôpital Purpan [Toulouse], Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital de Hautepierre [Strasbourg], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), CHU Limoges, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Le Mans (CH Le Mans), Hopital Saint-Louis [AP-HP] (AP-HP), Université de Rouen Normandie (UNIROUEN), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by grants by Association Neurofibromatoses et Recklinghausen Fondation CAP NF, Ligue Française Contre les Neurofibromatoses, INSERM (Nf1GeneModif project), and Ministère de l’Enseignement Supérieur et de la Recherche., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), 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), and Admin, Oskar

Subjects
Genotype-phenotype correlation, congenital, hereditary, and neonatal diseases and abnormalities, cardiovascular abnormalities, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, dysmorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, skeletal abnormalities, neurofibromatosis type 1, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, MPNSTs, learning disabilities, Neurofi-bromas, neoplasms, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, NF1 deletion, genotype–phenotype correlation, eye diseases, nervous system diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NF1, neurofibromas, NFs, malignant peripheral nerve sheath tumors, tumor predisposition
Abstract

Simple Summary Neurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Abstract Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.

Published
2021

42. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author

Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), 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), 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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [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 cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), 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 Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), 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)-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), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, 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), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, 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 Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe 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 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.

Published
2019

43. Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Author

Kirsley Chennen, Philippe Loget, Alix Clemenson, Elise Schaefer, Marie-Josée Perez, Elsa Nourisson, Laura Mary, Corinne Stoetzel, Bernard Gasser, Jean Muller, Annie Buenerd, Lucile Pinson, Louise Devisme, Florence Petit, Olivier Poch, Anne Sophie Leuvrey, Fabien Guimiot, Patrice Bouvagnet, Caroline Rooryck-Thambo, Brigitte Leroy, Manuela Antin, Tania Attié-Bitach, Jelena Martinovic, Fanny Pelluard, Raymonde Bouvier, Hélène Dollfus, Brigitte Gilbert-Dussardier, Elisabeth Alanio-Detton, Maria Cristina Antal, and Philippe Khau Van Kien

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Genotype, Biopsy, Autopsy, Disease, 030105 genetics & heredity, 03 medical and health sciences, Bardet–Biedl syndrome, Prenatal Diagnosis, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bardet-Biedl Syndrome, Alleles, Genetic Association Studies, Genetics (clinical), Cystic kidney, Fetus, Polydactyly, business.industry, medicine.disease, Ciliopathy, Phenotype, 030104 developmental biology, Amino Acid Substitution, Mutation, business
Abstract

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Published
2019

44. Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study

Author

Maryse Magen, Susana Quijano-Roy, Domitille Gras, Mathilde Nizon, Corinne Magdelaine, Catherine Vanhulle, Fabienne Giuliano, Eric Bieth, Véronique Manel, Damien Haye, Pascal Cintas, Florence Petit, Klaus Dieterich, Agnès Viguier, S. Peudenier, Valérie Lauwers-Cances, Mélanie Fradin, Claude Cances, Isabelle Desguerre, Arnaud Isapof, Michèle Mathieu-Dramard, and Michaël Jokic

Subjects
Male, 0301 basic medicine, Artificial ventilation, Pediatrics, medicine.medical_specialty, medicine.medical_treatment, Diaphragmatic breathing, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Respiratory system, Genetics (clinical), Retrospective Studies, Respiratory Distress Syndrome, Newborn, Palsy, Respiratory distress, business.industry, Infant, Newborn, Infant, Retrospective cohort study, Spinal muscular atrophy, Prognosis, medicine.disease, Respiration, Artificial, Hypotonia, DNA-Binding Proteins, Phenotype, 030104 developmental biology, Neurology, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Disease Progression, Female, France, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p

Published
2019

45. Novel Approach to Estimate Osteoarthritis Progression: Use of the Reliable Change Index in the Evaluation of Joint Space Loss

Author

Parsons, Camille M., Judge, Andrew, Leyland, Kirsten, Bruyere, Olivier, Dop, Florence Petit, Chapurlat, Roland, Reginster, Jean-yves, Edwards, Mark H., Dennison, Elaine M., Cooper, Cyrus, Inskip, Hazel, Reginster, J. -y., Christiansen, C., Delmas, P., Genant, H., Zacher, J., Bellamy, N., Speirs, C., Breart, G., Meyer, O., Gensburger, D., Arlot, M., Roux, J. -P., Deroisy, R., Sambrook, P., Leeb, B., Verbruggen, A., Bensen, W. G., Hala, T., Holm−bentzen, M., Valter, I., Chevalier, X., Swoboda, B., Adami, S., Kloppenburg, M., Grazuleviciute, E., Badurski, J., Branco, J., Nasonov, E., Navarro, F., Spector, T., Barnsley, L., Hall, S., Jones, G., Klestov, A., March, L., Nash, P., Romas, E., Will, R., Erlacher, L., Leeb, F. B., Resch, H., Rainer, F., Zamani, O., Appelboom, T., Devogelaer, J. P., Kvasz, A., Raeman, F., Beaulieu, A. D., Brown, J., Cividino, A. A., Morin, F., Olszynski, W. P., Raynauld, J. P., Thorne, J. C., Pavelka, K., Alexandersen, P., Hoeck, H. C., Holm-Bentzen, M., Lundqvist, P., Aim, L., Audouy, P., Beaunier, P., Benhamou, C. L., Berenbaum, F., Chabaud, E., Cohen-Solal, M., Delbecq, D., Euller-Ziegler, L., Fardellone, Patrice, Hilliquin, P., Jacquety, E., Jude, N., Lechevalier, D., Mouchet, J. C., Richette, P., Sainte Lorette, E., Schaeverbeke, T., Sebbah, A., Vignot, E., Brabant, T., Burm-Ester, G. R., Grifka, J., Mueller, P. E. M., Bianchi, G., Grassi, W., Di Matteo, L., Modena, V., Di Munno, O., Orto-Lani, S., Punzi, L., Zangari, M., Roorda, L. D., van Riel, P. L. C. M., Czerwinski, E., Gorecki, A., Tlustochowicz, W., da Silva, J. Canas, Gomes, J. A. Melo, Miranda, L. M., Radulescu, F., Alexeeva, L. I., Orlov-Morozov, A. V., Pikhlak, E. G., Pilyaev, V. G., Shostak, N. A., Shmidt, E. I., Zagorodniy, N. V., Rodriguez, L. Arboleya, Ruiz, P. Benito, Carmona, E. Chamizo, Estevez, E. Collantes, Herrero-Beaumont, G., Mola, E. Martin, Moreno, A., Hernandez, A. Naranjo, Sarabia, F. Navarro, Padrino, J. M., Palacios, C., Serna, A. Rodriguez, Ivorra, J. A. Roman, Torrijos, A., Abdulhakim, E., Arden, N., Birrell, F., Donnachie, H., Fraser, W., Keen, R., Sarmiento, R., Stone, M. D., Grp, Sekoia Study, Department of public health, Université de Liège, Service de Rhumatologie et Pathologie Osseuse [Lyon], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), World Health Organization (WHO), World Health Organization, University of Southampton, University of Bristol [Bristol], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Department of Public Health, Epidemiology and Health Economics, Center for Permafrost (CENPERM), Department of Geosciences and Natural Resource Management [Copenhagen] (IGN), Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Queen's University [Kingston, Canada], Department of Computer Science [Auckland], University of Auckland [Auckland], Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Antwerp (UA), Arkema (Arkema), Hutchinson SA, Chair of Aerodynamics and Fluid Mechanics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Leiden University Medical Center (LUMC), Universiteit Leiden, CEDOC - Department of Rheumatology, Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), CHLO/Hospital Egas Moniz, Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Radio and Space Plasma Physics Group [Leicester] (RSPP), University of Leicester, School of Environmental Sciences, University of Greenwich, Johns Hopkins University (JHU), University of Queensland [Brisbane], Université Laval [Québec] (ULaval), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Institute of Rheumatology, University Prague, Oskar Klein Centre [Stockholm], Stockholm University, Laboratoire de Réactivité de Surface (LRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Département de Rhumatologie, CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre Hospitalier Sud Francilien, Laboratoire d'Electronique, d'Informatique et d'Image [EA 7508] (Le2i), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aquitaine’s Care and Research organisation for inflammatory and Immune-Mediated diseases [CHU Bordeaux] (FHU ACRONIM), CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Department of Bone and Joint Diseases, Faculty of Medicine and Health Sciences, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Departamento de Construcción y Agronomía, Facultad de Ciencias Agrarias y Ambientales, University of Oxford, The University of Sydney, IUMEA, University of Las Palmas de Gran Canaria (ULPGC), the SEKOIA management team, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, Royaume-Uni], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], APH - Aging & Later Life, and Rehabilitation medicine

Subjects
Male, medicine.medical_specialty, Knee Joint, [SDV]Life Sciences [q-bio], Radiography, Osteoarthritis, Thiophenes, Placebo, Severity of Illness Index, Article, law.invention, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Rheumatology, Randomized controlled trial, Strontium ranelate, law, Internal medicine, Severity of illness, Medicine, Humans, skin and connective tissue diseases, Aged, Bone Density Conservation Agents, business.industry, Reproducibility of Results, Middle Aged, Osteoarthritis, Knee, medicine.disease, Multicenter study, Physical therapy, Disease Progression, Female, sense organs, business, medicine.drug
Abstract

Contains fulltext : 202254.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Osteoarthritis-related changes in joint space measurements over time are small and sensitive to measurement error. The Reliable Change Index (RCI) determines whether the magnitude of change observed in an individual can be attributed to true change. This study aimed to examine the RCI as a novel approach to estimating osteoarthritis progression. METHODS: Data were from 167 men and 392 women with knee osteoarthritis (diagnosed using the American College of Rheumatology criteria) randomized to the placebo arm of the 3-year Strontium Ranelate Efficacy in Knee Osteoarthritis trial (SEKOIA) and assessed annually. The RCI was used to determine whether the magnitude of change in joint space width (JSW) on radiographs between study years was likely to be true or due to measurement error. RESULTS: Between consecutive years, 57-69% of participants had an apparent decrease (change

Published
2019

47. Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia

Author

Yichi Zhang, Laura A. Lettice, Yin Shen, Elizabeth Lemos Silveira-Lucas, Aki Ushiki, Ilias Georgakopoulos-Soares, Michael J. Bamshad, Kirsty Jamieson, Florence Petit, Chenling Xiong, Jingjing Zhao, Nadav Ahituv, Lauren Kane, Deborah A. Nickerson, University of California [San Francisco] (UCSF), University of California, University of Edinburgh, University of Washington [Seattle], Hospital de Clínicas de Porto Alegre (HCPA), 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), Université de Lille, CHU Lille, University of California [San Francisco] [UC San Francisco], Hospital de Clínicas de Porto Alegre [HCPA], Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, University of California [San Francisco] (UC San Francisco), and University of California (UC)

Subjects
0301 basic medicine, Male, CCCTC-Binding Factor, Transcriptional regulatory elements, [SDV]Life Sciences [q-bio], genetic processes, General Physics and Astronomy, chemistry.chemical_compound, Mice, Congenital, 0302 clinical medicine, 2.1 Biological and endogenous factors, Developmental, Aetiology, Promoter Regions, Genetic, Sequence Deletion, Mice, Knockout, Multidisciplinary, Disease genetics, Gene Expression Regulation, Developmental, Exons, Phenotype, Chromatin, Cell biology, Enhancer Elements, Genetic, Embryo, Chromatin Immunoprecipitation Sequencing, Female, Hand Deformities, Congenital, Biotechnology, Foot Deformities, Foot Deformities, Congenital, Enhancer Elements, Science, Knockout, Locus (genetics), Development, Animals, Binding Sites, Disease Models, Animal, Embryo, Mammalian, Extremities, Genetic Loci, Genetic Testing, Hedgehog Proteins, Humans, Introns, Membrane Proteins, Species Specificity, Whole Genome Sequencing, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, 03 medical and health sciences, Genetic, Animal disease models, Genetics, Limb development, natural sciences, Enhancer, University of Washington Center for Mendelian Genomics, Gene knockout, Animal, Mammalian, Human Genome, General Chemistry, Hand Deformities, 030104 developmental biology, chemistry, Gene Expression Regulation, CTCF, Disease Models, 030217 neurology & neurosurgery, Function (biology), DNA
Abstract

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions., Acheiropodia is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development, but how these deletions lead to this phenotype is unknown. Here the authors use whole-genome sequencing, ChIP-seq, 4C-seq and DNA FISH to show that alterations in CTCF motifs are responsible via altered enhancer–promoter interactions.

Published
2021

48. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Author

Undiagnosed Diseases Network, Ilaria Parenti, Daphné Lehalle, Caroline Nava, Erin Torti, Elsa Leitão, Richard Person, Takeshi Mizuguchi, Naomichi Matsumoto, Mitsuhiro Kato, Kazuyuki Nakamura, SA (Stella) de Man, Heidi Cope, Vandana Shashi, Jennifer Friedman, Pascal Joset, Katharina Steindl, Anita Rauch, Irena Muffels, Peter M. van Hasselt, Florence Petit, Thomas Smol, Gwenaël Le Guyader, Frédéric Bilan, Arthur Sorlin, Antonio Vitobello, Christophe Philippe, I.M.B.H. (Ingrid) De Graaf - van de Laar, M.A. (Marjon) van Slegtenhorst, Philippe M. Campeau, Ping Yee Billie Au, Mitsuko Nakashima, Hirotomo Saitsu, Tatsuya Yamamoto, Yumiko Nomura, Raymond J. Louie, Michael J. Lyons, Amy Dobson, Astrid S. Plomp, M. Mahdi Motazacker, Frank J. Kaiser, Andrew T. Timberlake, Sabine A. Fuchs, Christel Depienne, Cyril Mignot, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Undiagnosed Diseases Network, Ilaria Parenti, Daphné Lehalle, Caroline Nava, Erin Torti, Elsa Leitão, Richard Person, Takeshi Mizuguchi, Naomichi Matsumoto, Mitsuhiro Kato, Kazuyuki Nakamura, SA (Stella) de Man, Heidi Cope, Vandana Shashi, Jennifer Friedman, Pascal Joset, Katharina Steindl, Anita Rauch, Irena Muffels, Peter M. van Hasselt, Florence Petit, Thomas Smol, Gwenaël Le Guyader, Frédéric Bilan, Arthur Sorlin, Antonio Vitobello, Christophe Philippe, I.M.B.H. (Ingrid) De Graaf - van de Laar, M.A. (Marjon) van Slegtenhorst, Philippe M. Campeau, Ping Yee Billie Au, Mitsuko Nakashima, Hirotomo Saitsu, Tatsuya Yamamoto, Yumiko Nomura, Raymond J. Louie, Michael J. Lyons, Amy Dobson, Astrid S. Plomp, M. Mahdi Motazacker, Frank J. Kaiser, Andrew T. Timberlake, Sabine A. Fuchs, Christel Depienne, Cyril Mignot, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, and Justin Alvey

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while

Published
2021
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49. Author response for 'Clinical and neuroimaging findings in 33 patients with MCAP syndrome: a survey to evaluate relevant endpoints for future clinical trials'

Author

Florence Petit, Juliette Mazereeuw-Hautier, Christine Coubes, Patricia Blanchet, Jenny Cornaton, Frederico Di Rocco, Fabienne Giuliano, Arthur Sorlin, Elodie Gautier, Laurent Guibaud, Renaud Touraine, Massimiliano Rossi, Christophe Philippe, Jean-Luc Alessandri, Joelle Roume, Patrick Edery, Gilles Morin, Christine Chiaverini, Diane Doummar, Michèle Mathieu-Dramard, Olivia Boccara, Philippe Khau Van Kien, Aurore Garde, Claire Nicolas, Maxime Luu, Lucile Pinson, Nicolas Chassaing, Fanny Morice-Picard, Christel Thauvin-Robinet, Rodolphe Dard, Cyril Mignot, Marc Bardou, V. Carmignac, Pierre Vabres, Alice Goldenberg, Laurence Faivre, Didier Lacombe, Annick Toutain, Stéphanie Arpin, Marjolaine Willems, and Anne-Claire Bursztejn

Subjects
Clinical trial, medicine.medical_specialty, Neuroimaging, business.industry, medicine, Intensive care medicine, business
Published
2020

50. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author

Julien Thevenon, Sophie Blesson, Sylvie Manouvrier Hanu, Chloé Quélin, Florence Fellmann, Nicolas Chassaing, Fabienne Giuliano, Laetitia Lambert, Caroline Rooryck-Thambo, Pierre-Simon Jouk, Sylvie Di Filippo, Alexandre Vasiljevic, Christine Francannet, Daphné Lehalle, Audrey Putoux, Anna‐Gaëlle Giguet‐Valard, Sophie Naudion, Salima El Chehadeh, Estelle Colin, Viorica Ciorna‐Monferrato, Bruno Reversade, Lionel Van Maldergem, Fanny Morice-Picard, Renaud Touraine, Sébastien Moutton, Jocelyne Attia, Laurent Pasquier, A. Vigouroux-Castera, Catherine Yardin, Tania Attié-Bitach, Carine Abel, Hui Liu, Sylvie Odent, Christelle Cabrol, Florence Petit, Philippe Khau Van Kien, Thomas Simonet, Catherine Vincent-Delorme, Jean Chiesa, Juliette Piard, Anne Bazin, Mélanie Fradin, Bertrand Isidor, Loubna El Zein, Patrice Bouvagnet, Marie-Pierre Brechard, Emmanuelle Szenker-Ravi, Sophie Scheidecker, Claire Beneteau, and ACS - Heart failure & arrhythmias

Subjects
Heart Defects, Congenital, Male, midline anomaly, Heterozygote, medicine.medical_specialty, Genetic counseling, Consanguinity, Heterotaxy Syndrome, Biology, DNA sequencing, 03 medical and health sciences, consanguinity, Genetics, medicine, Humans, Family, Family history, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, Obstetrics, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, heterotaxy, congenital heart defects, Cardiac malformations, Pedigree, fetus, Parental consanguinity, Cytogenetic Analysis, Mutation, Female, next-generation sequencing, Heterotaxy
Abstract

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.

Published
2020

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