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

6533b7d7fe1ef96bd1267cb2

RESEARCH PRODUCT

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

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

subject

Proband Male [SDV]Life Sciences [q-bio]intellectual deficiency MESH: NFI Transcription Factors chromatin remodeling Marfan Syndrome Craniofacial Abnormalities MESH: Child Intellectual disability MESH: Craniofacial Abnormalities MESH: Mental Retardation X-Linked Exome Child de novo variants Genetics (clinical)Exome sequencing Genetics MESH: Exome MESH: Middle Aged biology MESH: Genetic Predisposition to Disease Middle Aged NFIX MESH: Young Adult Female Adult MESH: Mutation Adolescent Chromatin remodeling MESH: Intellectual Disability MESH: Marfan Syndrome EHMT1 Young Adult MESH: Whole Exome Sequencing Intellectual Disability Exome Sequencing Genetics medicine Humans Genetic Predisposition to Disease marfanoid habitus Gene MESH: Neurodevelopmental Disorders MESH: Adolescent MESH: Humans Genetic heterogeneity MESH: Chromatin Assembly and Disassembly MESH: Histone-Lysine N-Methyltransferase MESH: Adult Histone-Lysine N-Methyltransferase medicine.disease Chromatin Assembly and Disassembly MESH: Male NFI Transcription Factors Neurodevelopmental Disorders Mutation biology.protein Mental Retardation X-Linked MESH: Female

description

PurposeMarfanoid 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.MethodsTo 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.ResultsWe 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.ConclusionWe 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.

year	journal	country	edition	language
2020-06-23	Journal of medical genetics

10.1136/jmedgenet-2019-106425 https://pubmed.ncbi.nlm.nih.gov/32277047