Recurrent de novo mutations implicate novel genes underlying simplex autism risk

O’Roak, Brian J.; Stessman, Holly A.F.; Boyle, Evan A.; Witherspoon, Kali; Martin, Beth; Lee, C.; Vives, Laura; Baker, Carl; Hiatt, Joseph; Da, Nickerson; Bernier, Raphael; Shendure, Jay; Eichler, Evan E.

doi:10.1038/ncomms6595

Cited by 292 publications

(271 citation statements)

References 33 publications

(71 reference statements)

Supporting

Mentioning

254

Contrasting

Unclassified

Order By: Relevance

“…1 Individuals 7 and 8 were identified in a large multicenter study to establish the contribution of de novo coding mutations to autism spectrum disorder. 18,19 Apart from the de novo mutation in WAC these two patients were not reported to have additional de novo mutations. 19 Database searches for copy number variations disrupting WAC We systematically searched for individuals with small deletions including WAC in our in-house database and international databases such as the database of the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) and the Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER).…”

Section: Diagnostic Exome Sequencingmentioning

confidence: 88%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

View full text Add to dashboard Cite

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

show abstract

Section: Diagnostic Exome Sequencingmentioning

confidence: 88%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

Section: Discussionmentioning

confidence: 99%

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

111

View full text Add to dashboard Cite

De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

show abstract

“…In mice, SynGAP1 accelerates the maturation of dendritic spines leading to disruptions in synaptic transmission and cognitive function [307][308][309][310] . Several de novo mutations of SYNGAP1 have also been associated with ASD 43,64,306,[311][312][313][314][315] . Together these results…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

Recurrent de novo mutations implicate novel genes underlying simplex autism risk

Cited by 292 publications

References 33 publications

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Dendritic spine actin cytoskeleton in autism spectrum disorder

Contact Info

Product

Resources

About