Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Abstract

Autism Genes, Again and Again Despite recent advances in sequencing technologies and their lowered costs—effective, highly sensitive, and specific sequencing of multiple genes of interest from large cohorts remains expensive. O'Roak et al. (p. 1619 ; published online 15 November) modified molecular inversion probe methods for target-specific capture and sequencing to resequence candidate genes in thousands of patients. The technique was applied to 44 candidate genes to identify de novo mutations in a large cohort of individuals with and without autism spectrum disorder. The analysis revealed several de novo mutations in genes that together contribute to 1% of sporadic autism spectrum disorders, supporting the notion that multiple genes underlie autism-spectrum disorders.

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

“…20,21 Targeted resequencing of WAC Upon identification of the de novo mutation in Individual 1, targeted resequencing was performed on a cohort of 2326 patients with unexplained ID using molecular inversion probes (MIPs) as described previously. 7 This cohort was selected from the in-house collection of the Department of Human Genetics of Radboud University Medical Center (Nijmegen, The Netherlands) containing patients with unexplained ID. Candidate loss-of-function mutations as well as highly conserved missense mutations (PhyloP45) were validated by standard Sanger sequencing approaches on DNA extracted from peripheral blood.…”

“…Targeted resequencing of WAC in an ID cohort identifies additional de novo mutations On the identification of multiple de novo loss-of-function mutations in WAC, we performed targeted resequencing of this gene in a cohort of over 2300 individuals with unexplained ID using MIPs as described before. 7 This cohort was selected from the in-house collection of the Department of Human Genetics of Radboud University Medical Center containing individuals with unexplained ID. All candidate loss-of-function mutations as well as highly conserved missense mutations (PhyloP45) were validated by standard Sanger sequencing approaches.…”

“…To establish the pathogenicity of mutations in such candidate ID genes, it is essential to identify additional individuals with an overlapping phenotype and a mutation in the same gene. [3][4][5] With increasing availability of WES in routine diagnostics 6 as well as technological advances facilitating targeted resequencing of candidate ID genes in larger cohorts of samples, 7 chances of finding such additional individuals are increasing. Furthermore, supporting evidence and insights into underlying mechanisms can be obtained from functional studies in cell or animal models.…”

Insights into the Genetic Foundations of Human Communication

“…The other syndrome results from mutations in TBR1, which is involved in cortical development and is co-expressed with FOXP2 in layer 6 of the cortex (Hevner et al 2001;Willsey et al 2013). Both syndromes are characterized by global developmental delay, ID, speech delay and varying degrees of language deficits (O'Roak et al 2011;Traylor et al 2012;Palumbo et al 2013;Palumbo et al 2014;O'Roak et al 2012;Belengeanu et al 2014;Le Fevre et al 2013;Bacon and Rappold 2012). In addition, autistic behaviors are found in all cases with TBR1 disruptions and in some individuals with FOXP1 mutations.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…For example, sequencing was performed on 2446 families with autistic patients from SSC to identify 44 candidate genes. In 6 genes, including CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1, recurrent disruptive mutations were detected (Table 3) [177]. Following this study, almost 3500 probands and their unaffected siblings were resequenced for 64 candidate genes in a case-control design.…”