30 results on '"Frédéric Tran Mau-Them"'
Search Results
2. Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis
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Frédéric Tran Mau-Them, Alexis Overs, Ange-Line Bruel, Romain Duquet, Mylene Thareau, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Arthur Sorlin, Hana Safraou, Sophie Nambot, Julian Delanne, Sebastien Moutton, Caroline Racine, Camille Engel, Melchior De Giraud d’Agay, Daphne Lehalle, Alice Goldenberg, Marjolaine Willems, Christine Coubes, David Genevieve, Alain Verloes, Yline Capri, Laurence Perrin, Marie-Line Jacquemont, Laetitia Lambert, Elodie Lacaze, Julien Thevenon, Nadine Hana, Julien Van-Gils, Charlotte Dubucs, Varoona Bizaoui, Marion Gerard-Blanluet, James Lespinasse, Sandra Mercier, Anne-Marie Guerrot, Isabelle Maystadt, Emilie Tisserant, Laurence Faivre, Christophe Philippe, Yannis Duffourd, and Christel Thauvin-Robinet
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GREP ,intellectual disability ,developmental anomalies ,genomic database ,diagnostic improvement ,exome sequencing (ES) ,Genetics ,QH426-470 - Abstract
Introduction: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Retrospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories.Patients and methods: We applied a reanalysis strategy based on intensive prospective bibliographic monitoring along with direct application of the GREP command-line tool (to “globally search for a regular expression and print matching lines”) in a large ES database. For 18 months, we submitted the same five keywords of interest [(intellectual disability, (neuro)developmental delay, and (neuro)developmental disorder)] to PubMed on a daily basis to identify recently published novel disease–gene associations or new phenotypes in genes already implicated in human pathology. We used the Linux GREP tool and an in-house script to collect all variants of these genes from our 5,459 exome database.Results: After GREP queries and variant filtration, we identified 128 genes of interest and collected 56 candidate variants from 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, GREP queries for only 128 genes over a period of 18 months permitted a causal diagnosis to be established in 21/2875 undiagnosed affected probands (0.7%).Conclusion: The GREP query strategy is efficient and less tedious than complete periodic reanalysis. It is an interesting reanalysis strategy to improve diagnosis.
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- 2023
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3. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool
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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
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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.
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- 2023
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4. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders
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Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, and Antonio Vitobello
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genome sequencing ,RNA-seq ,optical genome mapping ,long-read sequencing ,clinical diagnoses ,Biology (General) ,QH301-705.5 - Abstract
Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
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- 2023
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5. The different clinical facets of SYN1-related neurodevelopmental disorders
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Ilaria Parenti, Elsa Leitão, Alma Kuechler, Laurent Villard, Cyril Goizet, Cécile Courdier, Allan Bayat, Alessandra Rossi, Sophie Julia, Ange-Line Bruel, Frédéric Tran Mau-Them, Sophie Nambot, Daphné Lehalle, Marjolaine Willems, James Lespinasse, Jamal Ghoumid, Roseline Caumes, Thomas Smol, Salima El Chehadeh, Elise Schaefer, Marie-Thérèse Abi-Warde, Boris Keren, Alexandra Afenjar, Anne-Claude Tabet, Jonathan Levy, Anna Maruani, Ángel Aledo-Serrano, Waltraud Garming, Clara Milleret-Pignot, Anna Chassevent, Marije Koopmans, Nienke E. Verbeek, Richard Person, Rebecca Belles, Gary Bellus, Bonnie A. Salbert, Frank J. Kaiser, Laure Mazzola, Philippe Convers, Laurine Perrin, Amélie Piton, Gert Wiegand, Andrea Accogli, Francesco Brancati, Fabio Benfenati, Nicolas Chatron, David Lewis-Smith, Rhys H. Thomas, Federico Zara, Pasquale Striano, Gaetan Lesca, and Christel Depienne
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SYN1 ,synapsins ,reflex epilepsy ,genotype-phenotype correlation ,neurodevelopmental disorders ,autism spectrum disorders ,Biology (General) ,QH301-705.5 - Abstract
Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.
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- 2022
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6. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants
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Estelle Colin, Yannis Duffourd, Emilie Tisserant, Raissa Relator, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Hana Safraou, Julian Delanne, Nolwenn Jean-Marçais, Boris Keren, Bertrand Isidor, Marie Vincent, Cyril Mignot, Delphine Heron, Alexandra Afenjar, Solveig Heide, Anne Faudet, Perrine Charles, Sylvie Odent, Yvan Herenger, Arthur Sorlin, Sébastien Moutton, Jennifer Kerkhof, Haley McConkey, Martin Chevarin, Charlotte Poë, Victor Couturier, Valentin Bourgeois, Patrick Callier, Anne Boland, Robert Olaso, Christophe Philippe, Bekim Sadikovic, Christel Thauvin-Robinet, Laurence Faivre, Jean-François Deleuze, and Antonio Vitobello
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undiagnosed neurodevelopmental diseases ,genome sequencing ,transcriptome sequencing ,DNA methylation analysis ,translational research ,Biology (General) ,QH301-705.5 - Abstract
Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
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- 2022
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7. Atypical phenotype of a patient with Bardet–Biedl syndrome type 4
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Natacha Sloboda, Laetitia Lambert, Viorica Ciorna, Ange‐Line Bruel, Frédéric Tran Mau‐Them, Vladimir Gomola, Jean‐Louis Lemelle, Olivier Klein, Marie‐Christine Camoin‐Schweitzer, Marie Magnavacca, Carole Legagneur, Marie‐Laure Ezsto, Céline Bonnet, Christophe Philippe, and Bruno Leheup
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anal imperforation ,Bardet–Biedl syndrome ,genital anomalies ,sex assignment ,Genetics ,QH426-470 - Abstract
Abstract Background Bardet–Biedl syndrome (BBS) is a multisystemic disorder characterized by rod–cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. There is a large clinical and also genetic heterogeneity in BBS. Here, we report a patient with polydactyly, hyperechogenic kidneys increased in size with normal corticomedullary differentiation, anal imperforation, and malformation of genitals with presence of a genital tubercle with ventral urethral meatus associated with two unfused lateral genital swelling and absent urethral folds, in the context of 46, XY karyotype. Methods Karyotype and solo exome sequencing were performed to look for a genetic etiology for the features described in our patient. Results We identified a homozygous in‐frame deletion of exons 4 to 6 in the BBS4 gene (NM‐033028 (BBS4‐i001): c.[(157‐?)_(405 +?)del] p.(Ala53‐Trp135del), which is classified as pathogenic variant. This analysis allowed the molecular diagnosis of BBS type 4 in this patient. Conclusion Complex genital malformations are only reported in female BBS6 patients yet, and genital abnormalities and anal imperforation are not reported in male BBS4 patients to date. We discuss the possible hypotheses for this phenotype, including the phenotypic overlap between ciliopathies.
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- 2022
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8. The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders
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Julian Delanne, Ange-Line Bruel, Frédéric Huet, Sébastien Moutton, Sophie Nambot, Margot Grisval, Nada Houcinat, Paul Kuentz, Arthur Sorlin, Patrick Callier, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Daphné Lehalle, Salima El Chehadeh, Christine Francannet, Marine Lebrun, Laetitia Lambert, Marie-Line Jacquemont, Marion Gerard-Blanluet, Jean-Luc Alessandri, Marjolaine Willems, Julien Thevenon, Mondher Chouchane, Véronique Darmency, Clémence Fatus-Fauconnier, Sébastien Gay, Marie Bournez, Alice Masurel, Vanessa Leguy, Yannis Duffourd, Christophe Philippe, François Feillet, Laurence Faivre, and Christel Thauvin-Robinet
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Inherited metabolic disorders ,Exome sequencing ,Intellectual disability ,Developmental delay ,Genotype first ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable. Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
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- 2021
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9. Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly
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Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M.R. Taylor, Jennifer A. Sullivan, Ayat N. Asleh, Jaba Mitra, Mohamad A. Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A. Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R. Roeder, Rebecca Okashah Littlejohn, Harpreet K. Dibra, Philip J. Byrd, Grant S. Stewart, Bilgen B. Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E. VanNoy, Anne O’Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F. Buckley, Christel Thauvin, George K. Essien Umanah, Lionel Van Maldergem, James R. Lupski, Tony Roscioli, Valina L. Dawson, Ted M. Dawson, and Stylianos E. Antonarakis
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Genetics ,Genetics (clinical) - Published
- 2023
10. The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant
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Mio Aerden, Anne-Sophie Denommé-Pichon, Dominique Bonneau, Ange-Line Bruel, Julian Delanne, Bénédicte Gérard, Benoît Mazel, Christophe Philippe, Lucile Pinson, Clément Prouteau, Audrey Putoux, Frédéric Tran Mau-Them, Éléonore Viora-Dupont, Antonio Vitobello, Alban Ziegler, Amélie Piton, Bertrand Isidor, Christine Francannet, Pierre-Yves Maillard, Sophie Julia, Anais Philippe, Elise Schaefer, Saskia Koene, Claudia Ruivenkamp, Mariette Hoffer, Eric Legius, Miel Theunis, Boris Keren, Julien Buratti, Perrine Charles, Thomas Courtin, Mala Misra-Isrie, Mieke van Haelst, Quinten Waisfisz, Dagmar Wieczorek, Ariane Schmetz, Theresia Herget, Fanny Kortüm, Jasmin Lisfeld, François-Guillaume Debray, Nuria C. Bramswig, Isis Atallah, Heidi Fodstad, Guillaume Jouret, Berta Almoguera, Saoud Tahsin-Swafiri, Fernando Santos-Simarro, Maria Palomares-Bralo, Vanesa López-González, Maria Kibaek, Pernille M. Tørring, Alessandra Renieri, Lucia Pia Bruno, Katrin Õunap, Monica Wojcik, Tzung-Chien Hsieh, Peter Krawitz, Hilde Van Esch, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, and CCA - Cancer biology and immunology
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Genetics ,Genetics (clinical) - Abstract
Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.
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- 2023
11. Phenotypic characterization of seven individuals with <scp>Marbach–Schaaf</scp> neurodevelopmental syndrome
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Felix Marbach, Beata S. Lipska‐Ziętkiewicz, Agata Knurowska, Vincent Michaud, Henri Margot, James Lespinasse, Frédéric Tran Mau Them, Christine Coubes, Joohyun Park, Sarah Grosch, Cristiana Roggia, Ute Grasshoff, Louisa Kalsner, Anne‐Sophie Denommé‐Pichon, Alexandra Afenjar, Bénédicte Héron, Boris Keren, Pilar Caro, Christian P. Schaaf, Heidelberg University, University of Gdańsk (UG), Medical University of Gdańsk, 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), CHU Bordeaux [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], 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), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Tübingen, School of Medicine [University of Connecticut], University of Connecticut (UCONN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Baylor College of Medicine (BCM), Baylor University, and Admin, Oskar
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Adult ,Pain insensitivity ,Autism Spectrum Disorder ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Global developmental delay ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,Syndrome ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Cohort Studies ,[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,Phenotype ,Neurodevelopmental disorder ,PRKAR1B ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Neurodevelopmental Disorders ,Genetics ,Protein kinase a complex ,Animals ,Humans ,Genetics (clinical) - Abstract
International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.
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- 2022
12. O'Donnell-Luria-Rodan syndrome
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Camille Kumps, Heather Paterson, Benoît Funalot, Marjon van Slegtenhorst, Ingrid M.B.H. van de Laar, Robin Clark, Elliott H. Sherr, Marion Gérard, Jasmine L.F. Fung, Emanuela Argilli, Megan E. Rech, Antonio Vitobello, Christian Netzer, Christian P. Schaaf, Coranne D. Aarts-Tesselaar, Angela Abicht, Lennart Lessmeier, Brian H.Y. Chung, Anne-Sophie Denommé-Pichon, Jason Carmichael, Frédéric Tran Mau-Them, Andrea Superti-Furga, Marion Aubert Mucca, Marcus Cy Chan, Nicolas Chassaing, Christine Coubes, Anne H. O’Donnell-Luria, Lynn Pais, Colleen Kennedy, Daphné Lehalle, Maries Joseph, Kathleen A. Leppig, Florian Erger, John Karl de Dios, Lance H. Rodan, Marjolaine Willems, Subhadra Ramanathan, Clara Velmans, Eleina M. England, and Clinical Genetics
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0301 basic medicine ,Pediatrics ,Autism Spectrum Disorder ,behavioural ,Autism ,Medical and Health Sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual disability ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Exome ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Syndrome ,Biological Sciences ,Mental Health ,Autism spectrum disorder ,Cohort ,medicine.symptom ,medicine.medical_specialty ,Genetic counseling ,Intellectual and Developmental Disabilities (IDD) ,human genetics ,Article ,03 medical and health sciences ,Seizures ,Clinical Research ,Intellectual Disability ,Exome Sequencing ,medicine ,Genetics ,Humans ,business.industry ,Human Genome ,Macrocephaly ,Neurosciences ,medicine.disease ,Human genetics ,Megalencephaly ,Brain Disorders ,030104 developmental biology ,Neurodevelopmental Disorders ,Congenital Structural Anomalies ,mutation ,business ,030217 neurology & neurosurgery ,genetic counselling - Abstract
BackgroundO’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.
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- 2022
13. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders
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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.
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- 2023
14. Lessons from two series by physicians and caregivers’ self-reported data, and DNA methylation profile in DDX3X-Related Disorders
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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.
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- 2023
15. Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use
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Lauriane Le Collen, Brigitte Delemer, Christine Poitou, Martine Vaxillaire, Bénédicte Toussaint, Aurélie Dechaume, Alaa Badreddine, Mathilde Boissel, Mehdi Derhourhi, Karine Clément, Jean M. Petit, Frédéric Tran Mau-Them, Ange-Line Bruel, Christel Thauvin-Robinet, Alexandru Saveanu, Blandine Gatta Cherifi, Johanne Le Beyec-Le Bihan, Philippe Froguel, and Amélie Bonnefond
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Genetics (clinical) - Published
- 2023
16. A bi-allelic loss-of-function SARS1 variant in children with neurodevelopmental delay, deafness, cardiomyopathy, and decompensation during fever
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Jean-Marie Ravel, Jean-Louis Guéant, Natacha Dreumont, Marc Polivka, Jean-Baptiste Rivière, Frédéric Tran Mau-Them, Julien Thevenon, David Coelho, Gajja S. Salomons, Desirée E.C. Smith, Pauline Mosca, Emmanuelle Schmitt, Laurence Faivre, Gautam Kok, Marisa I. Mendes, Christel Thauvin-Robinet, Sabine A. Fuchs, Paul Kuentz, Arnaud Wiedemann, François Feillet, Clinical chemistry, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), Laboratory Genetic Metabolic Diseases, and Amsterdam Neuroscience
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Ataxia ,brain ,Cardiomyopathy ,SARS1 ,Loss of Heterozygosity ,Biology ,Amino Acyl-tRNA Synthetases ,chemistry.chemical_compound ,deafness ,death ,Genetics ,medicine ,Protein biosynthesis ,Missense mutation ,Humans ,Decompensation ,aminoacyl-tRNA synthetase ,Child ,tRNA ,Genetics (clinical) ,aminoacylation ,Aminoacyl tRNA synthetase ,medicine.disease ,Elongation factor ,chemistry ,intellectual disability ,Transfer RNA ,medicine.symptom ,Cardiomyopathies - Abstract
Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.
- Published
- 2021
17. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network
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Robert Olaso, Adeline Prost, Anne-Sophie Denommé-Pichon, Magali Gorce, Anne Boland, Mélanie Fradin, Magalie Barth, Mathilde Nizon, Antonio Vitobello, Dominique Bonneau, Bertrand Isidor, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Victor Couturier, Caroline Racine, Céline Besse, Marie Vincent, Bertrand Fin, Yline Capri, Alban Ziegler, Ange-Line Bruel, Yannis Duffourd, Christophe Philippe, P. Callier, Sébastien Moutton, Aurore Garde, Médéric Jeanne, Annick Toutain, Sophie Nambot, Delphine Bacq-Daian, Charlotte Poë, Emilie Tisserant, Aurélien Juven, Julien Van-Gils, Tiffany Busa, Laurent Pasquier, Sabine Sigaudy, Arthur Sorlin, Thibaud Jouan, Philippine Garret, Corinne Chantegret, Julian Delanne, Cyril Flamant, Alinoë Lavillaureix, Clement Prouteau, Paul Rollier, Laurence Faivre, and Jean-François Deleuze
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Protocol (science) ,Hospital network ,medicine.medical_specialty ,business.industry ,Infant, Newborn ,Infant ,Pilot Projects ,Context (language use) ,Disease ,Hospitals ,Article ,Intensive Care Units ,Intensive care ,Genetics ,medicine ,Etiology ,Feasibility Studies ,Humans ,Prospective Studies ,Duration (project management) ,Child ,Intensive care medicine ,business ,Genetics (clinical) ,Blood sampling - Abstract
Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.
- Published
- 2021
18. ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model
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Antonio Vitobello, Benoit Mazel, Vera G. Lelianova, Alice Zangrandi, Evelina Petitto, Jason Suckling, Vincenzo Salpietro, Robert Meyer, Miriam Elbracht, Ingo Kurth, Thomas Eggermann, Ouafa Benlaouer, Gurprit Lall, Alexander G. Tonevitsky, Daryl A. Scott, Katie M. Chan, Jill A. Rosenfeld, Sophie Nambot, Hana Safraou, Ange-Line Bruel, Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Christophe Philippe, Yannis Duffourd, Hui Guo, Andrea K. Petersen, Leslie Granger, Amy Crunk, Allan Bayat, Pasquale Striano, Federico Zara, Marcello Scala, Quentin Thomas, Andrée Delahaye, Jean-Madeleine de Sainte Agathe, Julien Buratti, Serguei V. Kozlov, Laurence Faivre, Christel Thauvin-Robinet, and Yuri Ushkaryov
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Adult ,Mice, Knockout ,Receptors, Peptide ,Autism Spectrum Disorder ,Haploinsufficiency ,Article ,Receptors, G-Protein-Coupled ,Disease Models, Animal ,Mice ,Neurodevelopmental Disorders ,Intellectual Disability ,Genetics ,Animals ,Humans ,Genetics (clinical) - Abstract
ADGRL1/latrophilin-1, a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe 10 individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all featuring heterozygous variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities while homozygous mice were non-viable. On a permissive background, the null allele also appeared at sub-Mendelian frequency, but many Adgrl1 null mice survived the gestation and reached adulthood. The Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological and behavioral abnormalities in mice and humans.
- Published
- 2022
19. Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study
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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)
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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
20. The Globally search for a Regular Expression and Print matching lines (GREP) strategy: an innovative reanalysis strategy combining bibliographic monitoring with fast GREP directly applied to a massive genomic database to rapidly improve diagnosis
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Frédéric Tran Mau Them, Alexis Overs, ange-line bruel, Romain Duquet, Mylene Thareau, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Arthur Sorlin, Hana Safraou, Sophie Nambot, Julian Delanne, Sebastien Moutton, Caroline RACINE, Camille Engel, Melchior D’agay, Daphné Lehalle, Alice Goldenberg, Marjolaine Willems, christine Coubes, David Geneviève, Alain Verloes, Yline CAPRI, Laurence Perrin, Marie-Line Jacquemont, Laetitia Lambert, Elodie Lacaze, Julien Thevenon, Nadine Hanna, Van-Gils Julien, Charlotte Dubucs, Varoona Bizaoui, Marion Gerard, James Lespinasse, Sandra Mercier, Anne-Marie Guerrot, Isabelle Maystadt, Emilie Tisserant, Laurence Faivre, Christophe Philippe, Yannis Duffourd, and Christel Thauvin-Robinet
- Subjects
genetic structures - Abstract
Purpose: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Prospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. We applied a reanalysis strategy based on intensive prospective bibliographic monitoring, and directly applied the Globally search for a Regular Expression and Print matching lines (GREP) command-line to a massive ES database. Methods: For 18 months, we submitted daily the same 5 keywords of interest (( intellectual disability, ( neuro)developmental delay, (neuro)developmental disorder)) to PubMed, to identify recently published, novel disease-gene associations, or new phenotypes in genes already implicated in human pathology. We used the Linux GREP command-line and an in-house script, to collect all variants in these genes from our 5459 exome database. Results: We grepped 128 genes and collected 56 candidate variants in 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals, and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, we confirmed pathogenicity in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP command-line is efficient, and less tedious than complete periodical reanalysis. It is an interesting reanalysis strategy to improve diagnosis.
- Published
- 2022
21. Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome
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Marco Angelozzi, Anirudha Karvande, Arnaud N Molin, Alyssa L Ritter, Jacqueline M M Leonard, Juliann M Savatt, Kristen Douglass, Scott M Myers, Mina Grippa, Dara Tolchin, Elaine Zackai, Sarah Donoghue, Anna C E Hurst, Maria Descartes, Kirstin Smith, Danita Velasco, Andrew Schmanski, Amy Crunk, Mari J Tokita, Iris M de Lange, Koen van Gassen, Hannah Robinson, Katie Guegan, Mohnish Suri, Chirag Patel, Marie Bournez, Laurence Faivre, Frédéric Tran-Mau-Them, Janice Baker, Noelle Fabie, K Weaver, Amelle Shillington, Robert J Hopkin, Daniela Q C.M Barge-Schaapveld, Claudia AL Ruivenkamp, Regina Bökenkamp, Samantha Vergano, Maria Noelia Seco Moro, Aranzazu Díaz de Bustamante, Vinod K Misra, Kelly Kennelly, Caleb Rogers, Jennifer Friedman, Kristen M Wigby, Jerica Lenberg, Claudio Graziano, Rebecca C Ahrens-Nicklas, and Veronique Lefebvre
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Micrognathism ,neonatal diseases ,congenital ,Syndrome ,DNA ,gene expression regulation ,Article ,SOXC Transcription Factors ,Phenotype ,Neurodevelopmental Disorders ,Intellectual Disability ,genetic variation ,Genetics ,Humans ,abnormalities ,Hand Deformities, Congenital ,hereditary ,Genetics (clinical) - Abstract
BackgroundA neurodevelopmental syndrome was recently reported in four patients withSOX4heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.MethodsWe newly identified 17 patients withSOX4variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes.ResultsAll variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including theSOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.ConclusionThese findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due toSOX4haploinsufficiency in neurogenesis and multiple other developmental processes.
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- 2022
22. Systematic analysis and prediction of genes associated with disorders on chromosome X
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Elsa Leitão, Christopher Schröder, Ilaria Parenti, Carine Dalle, Agnès Rastetter, Theresa Kühnel, Alma Kuechler, Sabine Kaya, Bénédicte Gérard, Elise Schaefer, Caroline Nava, Nathalie Drouot, Camille Engel, Juliette Piard, Bénédicte Duban-Bedu, Laurent Villard, Alexander P.A. Stegmann, Els K. Vanhoutte, Job A.J Verdonshot, Frank J. Kaiser, Frédéric Tran Mau-Them, Marcello Scala, Pasquale Striano, Suzanna G.M. Frints, Emanuela Argilli, Elliott H. Sherr, Fikret Elder, Julien Buratti, Boris Keren, Cyril Mignot, Delphine Héron, Jean-Louis Mandel, Jozef Gecz, Vera M. Kalscheuer, Bernhard Horsthemke, Amélie Piton, and Christel Depienne
- Abstract
Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
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- 2022
23. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects
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James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
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Male ,Bioinformatics ,Epilepsy ,0302 clinical medicine ,Neurodevelopmental disorder ,MESH: Child ,Intellectual disability ,Missense mutation ,MESH: Obesity ,MESH: Genetic Variation ,MESH: Nerve Tissue Proteins ,Child ,Genetics (clinical) ,MESH: Genetic Association Studies ,MESH: Heterozygote ,0303 health sciences ,MESH: Transcription Factors ,MESH: Infant ,3. Good health ,Phenotype ,MESH: Feeding and Eating Disorders ,MESH: Young Adult ,Child, Preschool ,MESH: Epilepsy ,Learning disability ,Female ,medicine.symptom ,Adult ,Heterozygote ,Adolescent ,Language delay ,Nerve Tissue Proteins ,Biology ,MESH: Phenotype ,MESH: Language Development Disorders ,Feeding and Eating Disorders ,Young Adult ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Language Development Disorders ,Obesity ,Genetic Association Studies ,030304 developmental biology ,MESH: Neurodevelopmental Disorders ,MESH: Adolescent ,MESH: Humans ,MESH: Child, Preschool ,Genetic Variation ,Infant ,MESH: Adult ,medicine.disease ,Human genetics ,MESH: Male ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Neurodevelopmental Disorders ,Autism ,MESH: Female ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.
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- 2022
24. Copy number variants calling from WES data through eXome hidden Markov model (XHMM) identifies additional 2.5% pathogenic genomic imbalances smaller than 30 kb undetected by array-CGH
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Emilie Tisserant, Antonio Vitobello, Davide Callegarin, Simon Verdez, Ange‐line Bruel, Ludwig Serge Aho Glele, Arthur Sorlin, Eleonore Viora‐Dupont, Marina Konyukh, Nathalie Marle, Sophie Nambot, Sébastien Moutton, Caroline Racine, Aurore Garde, Julian Delanne, Frédéric Tran‐Mau‐Them, Christophe Philippe, Paul Kuentz, Marlène Poulleau, Muriel Payet, Charlotte Poe, Christel Thauvin‐Robinet, Laurence Faivre, Anne‐Laure Mosca‐Boidron, Julien Thevenon, Yannis Duffourd, and Patrick Callier
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Comparative Genomic Hybridization ,DNA Copy Number Variations ,Intellectual Disability ,Exome Sequencing ,Genetics ,Humans ,Exome ,Genomics ,Genetics (clinical) - Abstract
It has been estimated that Copy Number Variants (CNVs) account for 10%-20% of patients affected by Developmental Disorder (DD)/Intellectual Disability (ID). Although array comparative genomic hybridization (array-CGH) represents the gold-standard for the detection of genomic imbalances, common Agilent array-CGH 4 × 180 kb arrays fail to detect CNVs smaller than 30 kb. Whole Exome sequencing (WES) is becoming the reference application for the detection of gene variants and makes it possible also to infer genomic imbalances at single exon resolution. However, the contribution of small CNVs in DD/ID is still underinvestigated. We made use of the eXome Hidden Markov Model (XHMM) software, a tool utilized by the ExAC consortium, to detect CNVs from whole exome sequencing data, in a cohort of 200 unsolved DD/DI patients after array-CGH and WES-based single nucleotide/indel variant analyses. In five out of 200 patients (2.5%), we identified pathogenic CNV(s) smaller than 30 kb, ranging from one to six exons. They included two heterozygous deletions in TCF4 and STXBP1 and three homozygous deletions in PPT1, CLCN2, and PIGN. After reverse phenotyping, all variants were reported as causative. This study shows the interest in applying sequencing-based CNV detection, from available WES data, to reduce the diagnostic odyssey of additional patients unsolved DD/DI patients and compare the CNV-detection yield of Agilent array-CGH 4 × 180kb versus whole exome sequencing.
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- 2021
25. A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort
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Philippine Garret, Martin Chevarin, Antonio Vitobello, Simon Verdez, Cyril Fournier, Alain Verloes, Emilie Tisserant, Pierre Vabres, Orlane Prevel, Christophe Philippe, Anne-Sophie Denommé-Pichon, Ange-Line Bruel, Frédéric Tran Mau-Them, Hana Safraou, Aïcha Boughalem, Jean-Marc Costa, Detlef Trost, Christel Thauvin-Robinet, Laurence Faivre, and Yannis Duffourd
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Genetics ,Genetics (clinical) - Abstract
About 0.3% of all variants are due to de novo mobile element insertions (MEIs). The massive development of next-generation sequencing has made it possible to identify MEIs on a large scale. We analyzed exome sequencing (ES) data from 3232 individuals (2410 probands) with developmental and/or neurological abnormalities, with MELT, a tool designed to identify MEIs. The results were filtered by frequency, impacted region and gene function. Following phenotype comparison, two candidates were identified in two unrelated probands. The first mobile element (ME) was found in a patient referred for poikilodermia. A homozygous insertion was identified in the FERMT1 gene involved in Kindler syndrome. RNA study confirmed its pathological impact on splicing. The second ME was a de novo Alu insertion in the GRIN2B gene involved in intellectual disability, and detected in a patient with a developmental disorder. The frequency of de novo exonic MEIs in our study is concordant with previous studies on ES data. This project, which aimed to identify pathological MEIs in the coding sequence of genes, confirms that including detection of MEs in the ES pipeline can increase the diagnostic rate. This work provides additional evidence that ES could be used alone as a diagnostic exam.
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- 2021
26. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics
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Arthur Sorlin, Antonio Vitobello, Benoit Daubail, Christel Thauvin-Robinet, Marie Hervieu-Bègue, Laurence Faivre, Agnès Fromont, Ange-Line Bruel, Frédéric Tran Mau-Them, Thibault Moreau, Julian Delanne, Guy-Victor Osseby, Quentin Thomas, Patrick Callier, Christophe Philippe, Sébastien Moutton, Maurice Giroud, Anne-Sophie Denommé-Pichon, Agnès Jacquin-Piques, Sophie Nambot, Yannis Duffourd, Philippine Garret, Y Béjot, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Neurophysiologie Clinique (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
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Proband ,Pediatrics ,medicine.medical_specialty ,Movement disorders ,Neurology ,Neurodegeneration with brain iron accumulation ,[SDV]Life Sciences [q-bio] ,Encephalopathy ,Neurogenetics ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Genetics ,Humans ,Medicine ,Exome ,Clinical significance ,030212 general & internal medicine ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,business.industry ,medicine.disease ,Phenotype ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,Nervous System Diseases ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.
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- 2021
27. P764: RNA sequencing improves assessment of variants of uncertain significance from fetal genome and exome sequencing
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Atteeq Rehman, Amanda Thomas-Wilson, Frederic Tran Mau-Them, Leandra Tolusso, Avinash Abyankar, Saurav Guha, Volkan Okur, Vanessa Felice, Robert Hopkin, Ashley Wilson, Ted Han, Qiaoning Guan, Jessica Giordano, Anne-Claire Bréhin, Ronald Wapner, and Vaidehi Jobanputra
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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28. Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome
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Yosuke Nishio, Kohji Kato, Frederic Tran Mau-Them, Hiroshi Futagawa, Chloé Quélin, Saori Masuda, Antonio Vitobello, Shiomi Otsuji, Hossam H. Shawki, Hisashi Oishi, Christel Thauvin-Robinet, Toshiki Takenouchi, Kenjiro Kosaki, Yoshiyuki Takahashi, and Shinji Saitoh
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Genetics ,QH426-470 - Abstract
Summary: MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis.
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- 2023
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29. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis
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Charlotte Gehin, Museer A. Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M. Adeyemi, Erica H. Gerkes, Alexander P.A. Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R. Jones, Stefano Zamuner, Luciano A. Abriata, Vidya Kunnathully, Brandon E. Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W. van Bon, Rolph Pfundt, Marjolein H. Willemsen, Jolanda H. Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R. Fagerberg, Christoph P. Beier, Martin J. Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S. Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis B.R. Maddocks, Jennifer M. Bain, Musadiq A. Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L. Champaigne, Michael J. Friez, Ellen B. Richardson, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Yask Gupta, Tze Y. Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E. Burke, Ana Marjia Jakšić, Brian D. McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D’Angelo, and Vincenzo A. Gennarino
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Cell biology ,Genetics ,Medicine - Abstract
Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
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- 2023
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30. Interest of exome sequencing trio‐like strategy based on pooled parental DNA for diagnosis and translational research in rare diseases
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Frederic Tran Mau‐Them, Yannis Duffourd, Antonio Vitobello, Ange‐Line Bruel, Anne‐Sophie Denommé‐Pichon, Sophie Nambot, Julian Delanne, Sebastien Moutton, Arthur Sorlin, Orphanomix Physician’s Group, Victor Couturier, Valentin Bourgeois, Martin Chevarin, Charlotte Poe, Anne‐Laure Mosca‐Boidron, Patrick Callier, Hana Safraou, Laurence Faivre, Christophe Philippe, and Christel Thauvin‐Robinet
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cost effectiveness ,exome sequencing ,rare diseases ,trio‐like strategy ,parental‐pool strategy ,Genetics ,QH426-470 - Abstract
Abstract Background Exome sequencing (ES) has become the most powerful and cost‐effective molecular tool for deciphering rare diseases with a diagnostic yield approaching 30%–40% in solo‐ES and 50% in trio‐ES. We applied an innovative parental DNA pooling method to reduce the parental sequencing cost while maintaining the diagnostic yield of trio‐ES. Methods We pooled six (Agilent‐CRE‐v2–100X) or five parental DNA (TWIST‐HCE–70X) aiming to detect allelic balance around 8–10% for heterozygous status. The strategies were applied as second‐tier (74 individuals after negative solo‐ES) and first‐tier approaches (324 individuals without previous ES). Results The allelic balance of parental‐pool variants was around 8.97%. Sanger sequencing uncovered false positives in 1.5% of sporadic variants. In the second‐tier approach, we evaluated than two thirds of the Sanger validations performed after solo‐ES (41/59–69%) would have been saved if the parental‐pool segregations had been available from the start. The parental‐pool strategy identified a causative diagnosis in 18/74 individuals (24%) in the second‐tier and in 116/324 individuals (36%) in the first‐tier approaches, including 19 genes newly associated with human disorders. Conclusions Parental‐pooling is an efficient alternative to trio‐ES. It provides rapid segregation and extension to translational research while reducing the cost of parental and Sanger sequencing.
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- 2021
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