RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP 466
OP 474
DO 10.1136/jmedgenet-2019-106425
VO 57
IS 7
A1 Chevarin, Martin
A1 Duffourd, Yannis
A1 A. Barnard, Rebecca
A1 Moutton, Sébastien
A1 Lecoquierre, François
A1 Daoud, Fatma
A1 Kuentz, Paul
A1 Cabret, Caroline
A1 Thevenon, Julien
A1 Gautier, Elodie
A1 Callier, Patrick
A1 St-Onge, Judith
A1 Jouan, Thibaud
A1 Lacombe, Didier
A1 Delrue, Marie Ange
A1 Goizet, Cyril
A1 Morice-Picard, Fanny
A1 Van-Gils, Julien
A1 Munnich, Arnold
A1 Lyonnet, Stanislas
A1 Cormier-Daire, Valérie
A1 Baujat, Geneviève
A1 Holder, Muriel
A1 Petit, Florence
A1 Leheup, Bruno
A1 Odent, Sylvie
A1 Jouk, Pierre-Simon
A1 Lopez, Gipsy
A1 Geneviève, David
A1 Collignon, Patrick
A1 Martin-Coignard, Dominique
A1 Jacquette, Aurélia
A1 Perrin, Laurence
A1 Putoux, Audrey
A1 Sarrazin, Elisabeth
A1 Amarof, Khadija
A1 Missotte, Isabelle
A1 Coubes, Christine
A1 Jagadeesh, Sujatha
A1 Lapi, Elisabetta
A1 Demurger, Florence
A1 Goldenberg, Alice
A1 Doco-Fenzy, Martine
A1 Mignot, Cyril
A1 Héron, Delphine
A1 Jean-Marçais, Nolwenn
A1 Masurel, Alice
A1 El Chehadeh, Salima
A1 Marle, Nathalie
A1 Huet, Frédéric
A1 Binquet, Christine
A1 Collod-Beroud, Gwenaëlle
A1 Arnaud, Pauline
A1 Hanna, Nadine
A1 Boileau, Catherine
A1 Jondeau, Guillaume
A1 Olaso, Robert
A1 Lechner, Doris
A1 Poe, Charlotte
A1 Assoum, Mirna
A1 Carmignac, Virginie
A1 Duplomb, Laurence
A1 Tran Mau-Them, Frédéric
A1 Philippe, Christophe
A1 Vitobello, Antonio
A1 Bruel, Ange-Line
A1 Boland, Anne
A1 Deleuze, Jean-François
A1 Thauvin-Robinet, Christel
A1 Rivière, Jean-Baptiste
A1 O'Roak, Brian J
A1 Faivre, Laurence
YR 2020
UL http://jmg.bmj.com/content/57/7/466.abstract
AB 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.