Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

By Brian J. O'Roak, P. Deriziotis, Choli Lee, Laura Vives, Jerrod J Schwartz, S. Girirajan, E. Karakoç, Alexandra P. MacKenzie, Sarah B. H. Ng, Carl A. Baker and 6 more. Nature Genetics, 2011

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Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.

Subfields: Cognitive Neuroscience, Epidemiology, Genetics

View Paper: https://www.semanticscholar.org/paper/d3b882ff67b7f0a1f65501cd69837a211ae884df

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Citations in the corpus

Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications (2014, methodology): “Several recent studies have successfully identified disease-causing de novo mutations using sequence data from parent-offspring trios, in both exomes 29–31 and whole genomes 32,33 .”
A general framework for estimating the relative pathogenicity of human genetic variants (2014, background): “First, we analyzed de novo exome variants (SNVs and indels) identified in children with autism spectrum disorders 30–34 (ASD) and intellectual disability 35,36 (ID) along with unaffected siblings or controls, including 88 nonsense, 1,015 missense, 359 synonymous, 32 canonical splice site, and 150…”
Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data (2015, background): “The trio format is a common familial arrangement in sequencing studies undertaken to uncover the genetic basis for a known disease or to assist in disease diagnosis [39,40].”
Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation (2012, positive): “We used sites from this work, Conrad et al. (2011), Iossifov et al. (2012), Neale et al. (2012), O’Roak et al. (2011, 2012), and Sanders et al. (2012), which were lifted over from hg19 to hg18 coordinates, in the calculation of these mutation rates (Figure 4).”
A systematic approach to assessing the clinical significance of genetic variants (2013, background): “The de novo point mutation rate is ∼1 per exome (32), consistent with an average rate of 1.”
Exome sequencing as a tool for Mendelian disease gene discovery (2011, positive): “Sequencing of trios has been used to find de novo mutations that are responsible for rare Mendelian disorders (for example, Schinzel–Giedion syndrome 37 ) as well as for genetically heterogeneous disorders, such as intellectual disabilities 45 , schizophrenia 46 and autism 47 .”