TY - JOUR T1 - Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability JF - Journal of Medical Genetics JO - J Med Genet SP - 466 LP - 474 DO - 10.1136/jmedgenet-2019-106425 VL - 57 IS - 7 AU - Martin Chevarin AU - Yannis Duffourd AU - Rebecca A. Barnard AU - Sébastien Moutton AU - François Lecoquierre AU - Fatma Daoud AU - Paul Kuentz AU - Caroline Cabret AU - Julien Thevenon AU - Elodie Gautier AU - Patrick Callier AU - Judith St-Onge AU - Thibaud Jouan AU - Didier Lacombe AU - Marie Ange Delrue AU - Cyril Goizet AU - Fanny Morice-Picard AU - Julien Van-Gils AU - Arnold Munnich AU - Stanislas Lyonnet AU - Valérie Cormier-Daire AU - Geneviève Baujat AU - Muriel Holder AU - Florence Petit AU - Bruno Leheup AU - Sylvie Odent AU - Pierre-Simon Jouk AU - Gipsy Lopez AU - David Geneviève AU - Patrick Collignon AU - Dominique Martin-Coignard AU - Aurélia Jacquette AU - Laurence Perrin AU - Audrey Putoux AU - Elisabeth Sarrazin AU - Khadija Amarof AU - Isabelle Missotte AU - Christine Coubes AU - Sujatha Jagadeesh AU - Elisabetta Lapi AU - Florence Demurger AU - Alice Goldenberg AU - Martine Doco-Fenzy AU - Cyril Mignot AU - Delphine Héron AU - Nolwenn Jean-Marçais AU - Alice Masurel AU - Salima El Chehadeh AU - Nathalie Marle AU - Frédéric Huet AU - Christine Binquet AU - Gwenaëlle Collod-Beroud AU - Pauline Arnaud AU - Nadine Hanna AU - Catherine Boileau AU - Guillaume Jondeau AU - Robert Olaso AU - Doris Lechner AU - Charlotte Poe AU - Mirna Assoum AU - Virginie Carmignac AU - Laurence Duplomb AU - Frédéric Tran Mau-Them AU - Christophe Philippe AU - Antonio Vitobello AU - Ange-Line Bruel AU - Anne Boland AU - Jean-François Deleuze AU - Christel Thauvin-Robinet AU - Jean-Baptiste Rivière AU - Brian J O'Roak AU - Laurence Faivre Y1 - 2020/07/01 UR - http://jmg.bmj.com/content/57/7/466.abstract N2 - Purpose Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.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. ER -