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

Authors:
Holly N Cukier
Holly N Cukier
University of Miami
United States
Nicole D Dueker
Nicole D Dueker
John P. Hussman Institute for Human Genomics
Susan H Slifer
Susan H Slifer
Duke University Medical Center
United States
Joycelyn M Lee
Joycelyn M Lee
John P. Hussman Institute for Human Genomics
United States
Patrice L Whitehead
Patrice L Whitehead
John P. Hussman Institute for Human Genomics
United States
Ioanna Konidari
Ioanna Konidari
University of Miami
United States

Mol Autism 2014 Jan 10;5(1). Epub 2014 Jan 10.

John P, Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, BRB-314 (M860), Miami, FL, USA.

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.

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http://dx.doi.org/10.1186/2040-2392-5-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896704PMC
January 2014
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