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Article Dans Une Revue Journal of Medical Genetics Année : 2020

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

Martin Chevarin (1) , Yannis Duffourd (1, 2) , Rebecca a Barnard , Sébastien Moutton (1, 3, 4) , François Lecoquierre (1) , Fatma Daoud (1) , Paul Kuentz (1, 2) , Caroline Cabret (1) , Julien Thevenon (1, 3) , Elodie Gautier (2) , Patrick Callier (1, 2) , Judith St-Onge (1) , Thibaud Jouan (1) , Didier Lacombe (4) , Marie Ange Delrue (4) , Cyril Goizet (4) , Fanny Morice-Picard (4) , Julien Van-Gils (4) , Arnold Munnich (5, 6) , Stanislas Lyonnet (5, 6) , Valérie Cormier-Daire (5, 6) , Geneviève Baujat (5, 6) , Muriel Holder (7) , Florence Petit (7) , Bruno Leheup (8) , Sylvie Odent (9) , Pierre-Simon Jouk (10) , Gipsy Lopez (10) , David Geneviève (11) , Patrick Collignon , Dominique Martin-Coignard (12) , Aurélia Jacquette (13) , Laurence Perrin (14) , Audrey Putoux (15) , Elisabeth Sarrazin (16, 17) , Khadija Amarof (16, 17) , Isabelle Missotte (18) , Christine Coubes (11) , Sujatha Jagadeesh , Elisabetta Lapi , Florence Demurger , Alice Goldenberg (19) , Martine Doco-Fenzy (20, 21) , Cyril Mignot , Delphine Héron , Nolwenn Jean-Marçais (2) , Alice Masurel , Salima El Chehadeh , Nathalie Marle (1, 2) , Frédéric Huet (2) , Christine Binquet (3) , Gwenaëlle Collod-Beroud (22) , Pauline Arnaud (23) , Nadine Hanna (23) , Catherine Boileau (23) , Guillaume Jondeau (23) , Robert Olaso (24, 25, 26) , Doris Lechner (24, 25, 26) , Charlotte Poe (1) , Mirna Assoum (1) , Virginie Carmignac (1) , Laurence Duplomb (1) , Frédéric Tran Mau-Them (1) , Christophe Philippe (1) , Antonio Vitobello (1) , Ange-Line Bruel (1) , Anne Boland (24, 25, 26) , Jean-François Deleuze (24, 25, 26) , Christel Thauvin-Robinet (1, 2) , Jean-Baptiste Rivière (1, 2) , Brian O'Roak , Laurence Faivre (2, 3, 1)
Rebecca a Barnard
  • Fonction : Auteur
François Lecoquierre
Didier Lacombe
  • Fonction : Auteur
Marie Ange Delrue
  • Fonction : Auteur
Cyril Goizet
  • Fonction : Auteur
Fanny Morice-Picard
  • Fonction : Auteur
Julien Van-Gils
  • Fonction : Auteur
Patrick Collignon
  • Fonction : Auteur
Sujatha Jagadeesh
  • Fonction : Auteur
Elisabetta Lapi
  • Fonction : Auteur
Florence Demurger
  • Fonction : Auteur
Alice Goldenberg
  • Fonction : Auteur
Cyril Mignot
  • Fonction : Auteur
Delphine Héron
  • Fonction : Auteur
Alice Masurel
  • Fonction : Auteur
Salima El Chehadeh
Christophe Philippe
  • Fonction : Auteur
  • PersonId : 761163
  • IdRef : 083945237
Brian O'Roak
  • Fonction : Auteur

Résumé

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.
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.
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Dates et versions

hal-03619568 , version 1 (25-03-2022)

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Citer

Martin Chevarin, Yannis Duffourd, Rebecca a Barnard, Sébastien Moutton, François Lecoquierre, et al.. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability. Journal of Medical Genetics, 2020, 57 (7), pp.466-474. ⟨10.1136/jmedgenet-2019-106425⟩. ⟨hal-03619568⟩
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