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

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

doi:10.1186/2040-2392-5-1

Abstract

BackgroundAutism 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.MethodsTo 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.ResultsWe 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).ConclusionsBy 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.

Highlights

Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior
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
We examined our results for overlap in genes previously reported in the literature and publically available databases to be associated with ASDs and other neurological disorders including attention deficit hyperactivity disorder (ADHD), bipolar disorder, developmental delay, epilepsy, intellectual disability, major depression, obsessive compulsive disorder, schizophrenia, speech disorders, and Tourette syndrome [2,36,37]

Summary

Introduction

Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. ASDs occur in approximately one of every 88 individuals and genetic studies to date demonstrate that the ASD etiology is highly complex with over 100 candidate genes being implicated in ASD etiology through linkage, association, and candidate gene studies [2,3]. This genetic complexity is compounded by the fact that many families present with private and rare alterations and that known pathogenic alterations can result in a variety of clinical consequences [4,5,6]. Our strategy discovered potentially damaging alterations in both known and novel ASD candidate genes, as well as in genes that carry variations known to be pathogenic in other neurological disorders

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