Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

By Brian J. O'Roak, Laura Vives, Wenqing Fu, Jarrett D. Egertson, I. Stanaway, I. G. Phelps, G. Carvill, Akash Kumar, Choli Lee, K. Ankenman and 16 more. Science, 2012

1,254 citations recorded by the source corpus.

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. Large-scale human autism candidate gene resequencing implicates de novo mutations in six genes in ~1% of sporadic cases. Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin–chromatin-remodeling network to ASD etiology.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b250fc7542307e0719e62c1b17e67d6bb32f71ce

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Citations in the corpus

Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015, methodology): “Genes in this subnetwork were evaluated in a larger cohort in a targeted sequencing study 120 , which identified more risk variants compared with chance and demonstrated that PPI connectivity can be a predictor of ASD risk mutations.”
A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships (2018, background): “PTEN mutations have been identified in macrocephaly cohorts of individuals with formal ASD diagnoses or developmental delay (DD)/intellectual disability (ID)(13,21,22) as well as idiopathic ASD.(14,23,24) It is currently impossible to predict the phenotypic outcome of a given PTEN mutation.”
Disruptive CHD8 mutations define a subtype of autism early in development (2014, methodology): “In total, 105 overlapping probes covering the coding sequence and splice junctions were included in the assay as part of a larger set of probes (O’Roak et al., 2012a).”
Advancing the understanding of autism disease mechanisms through genetics (2016, neutral): “In general, current estimates of the significance of an association between a mutation and ASD are based on comparing the frequency of the observed mutations in patients to the expected rate at which null mutations would occur in that gene 47,50,51 .”
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 (2013, neutral): “EME 5 1 (20) EOEE 39 8 (21) Epilepsy aphasia 27 3 (11) FIRES 12 0 Infantile spasms 81 4 (5) LKS 3 0 LGS 40 5 (13) MAE 81 3 (4) Ohtahara syndrome 4 2 (50) Total 500 52 (10)”