Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)466-474
Number of pages9
JournalJournal of medical genetics
Issue number7
StatePublished - Jul 1 2020


  • chromatin remodeling
  • de novo variants
  • exome sequencing
  • intellectual deficiency
  • marfanoid habitus

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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