title: De novo mutations in moderate or severe intellectual disability.
abstract: Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada; Division of Pediatric Neurology, Montreal Children's Hospital, Montreal, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Jose-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Nassif
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Amirthagowri
authors.initials: A
authors.lastname: Ambalavanan
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Ousmane
authors.initials: O
authors.lastname: Diallo
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Edouard
authors.initials: E
authors.lastname: Henrion
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Fougerat
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.affiliation: Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Venkateswaran
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada; Department of Pediatrics and Department of Neurosciences, University of Montreal, Montreal, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D018389:Codon, Nonsense; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D016368:Frameshift Mutation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D017354:Point Mutation; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense