Dataset Information

Using whole-exome sequencing to identify inherited causes of autism.

ABSTRACT: Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

SUBMITTER: Yu TW

PROVIDER: S-EPMC3694430 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Publications

Using whole-exome sequencing to identify inherited causes of autism.

Yu Timothy W TW Chahrour Maria H MH Coulter Michael E ME Jiralerspong Sarn S Okamura-Ikeda Kazuko K Ataman Bulent B Schmitz-Abe Klaus K Harmin David A DA Adli Mazhar M Malik Athar N AN D'Gama Alissa M AM Lim Elaine T ET Sanders Stephan J SJ Mochida Ganesh H GH Partlow Jennifer N JN Sunu Christine M CM Felie Jillian M JM Rodriguez Jacqueline J Nasir Ramzi H RH Ware Janice J Joseph Robert M RM Hill R Sean RS Kwan Benjamin Y BY Al-Saffar Muna M Mukaddes Nahit M NM Hashmi Asif A Balkhy Soher S Gascon Generoso G GG Hisama Fuki M FM LeClair Elaine E Poduri Annapurna A Oner Ozgur O Al-Saad Samira S Al-Awadi Sadika A SA Bastaki Laila L Ben-Omran Tawfeg T Teebi Ahmad S AS Al-Gazali Lihadh L Eapen Valsamma V Stevens Christine R CR Rappaport Leonard L Gabriel Stacey B SB Markianos Kyriacos K State Matthew W MW Greenberg Michael E ME Taniguchi Hisaaki H Braverman Nancy E NE Morrow Eric M EM Walsh Christopher A CA

Neuron 20130101 2

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes ( ...[more]

PMID: 23352163

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Project description:Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.

Dataset Information

Using whole-exome sequencing to identify inherited causes of autism.

Publications

Using whole-exome sequencing to identify inherited causes of autism.

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