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