Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.
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Chevarin Martin, Duffourd Yannis, A Barnard Rebecca, Moutton Sébastien, Lecoquierre François, Daoud Fatma, Kuentz Paul, Cabret Caroline, Thevenon Julien, Gautier Elodie, Callier Patrick, St-Onge Judith, Jouan Thibaud, Lacombe Didier, Delrue Marie Ange, Goizet Cyril, Morice-Picard Fanny, Van-Gils Julien, Munnich Arnold, Lyonnet Stanislas, Cormier-Daire Valérie, Baujat Geneviève, Holder Muriel, Petit Florence, Leheup Bruno, Odent Sylvie, Jouk Pierre-Simon, Lopez Gipsy, Geneviève David, Collignon Patrick, Martin-Coignard Dominique, Jacquette Aurélia, Perrin Laurence, Putoux Audrey, Sarrazin Elisabeth, Amarof Khadija, Missotte Isabelle, Coubes Christine, Jagadeesh Sujatha, Lapi Elisabetta, Demurger Florence, Goldenberg Alice, Doco-Fenzy Martine, Mignot Cyril, Héron Delphine, Jean-Marçais Nolwenn, Masurel Alice, El Chehadeh Salima, Marle Nathalie, Huet Frédéric, Binquet Christine, Collod-Beroud Gwenaëlle, Arnaud Pauline, Hanna Nadine, Boileau Catherine, Jondeau Guillaume, Olaso Robert, Lechner Doris, Poe Charlotte, Assoum Mirna, Carmignac Virginie, Duplomb Laurence, Tran Mau-Them Frédéric, Philippe Christophe, Vitobello Antonio, Bruel Ange-Line, Boland Anne, Deleuze Jean-François, Thauvin-Robinet Christel, Rivière Jean-Baptiste, O'Roak Brian J, Faivre Laurence
Аннотация
METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.
RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.
CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.