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Molecular Autism
Published in: Molecular Autism 1/2014

Open Access 01-12-2014 | Research

Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders

Authors: Holly N Cukier, Nicole D Dueker, Susan H Slifer, Joycelyn M Lee, Patrice L Whitehead, Eminisha Lalanne, Natalia Leyva, Ioanna Konidari, Ryan C Gentry, William F Hulme, Derek Van Booven, Vera Mayo, Natalia K Hofmann, Michael A Schmidt, Eden R Martin, Jonathan L Haines, Michael L Cuccaro, John R Gilbert, Margaret A Pericak-Vance

Published in: Molecular Autism | Issue 1/2014

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Abstract

Background

Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered.

Methods

To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized.

Results

We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10-5).

Conclusions

By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
Appendix
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Metadata
Title
Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders
Authors
Holly N Cukier
Nicole D Dueker
Susan H Slifer
Joycelyn M Lee
Patrice L Whitehead
Eminisha Lalanne
Natalia Leyva
Ioanna Konidari
Ryan C Gentry
William F Hulme
Derek Van Booven
Vera Mayo
Natalia K Hofmann
Michael A Schmidt
Eden R Martin
Jonathan L Haines
Michael L Cuccaro
John R Gilbert
Margaret A Pericak-Vance
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2014
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-5-1

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