Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability. Issue 7 (10th April 2020)

• Record Type: Journal Article
• Authors: 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;
• Is Part Of: Journal of medical genetics. Volume 57:Issue 7(2020)
• Page Start: 466
• Page End: 474
• Publication Date: 2020-04-10
• Subjects: marfanoid habitus -- intellectual deficiency -- exome sequencing -- chromatin remodeling -- de novo variants; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2019-106425
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.