title: Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.
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.
authors.forename: Holly N
authors.initials: HN
authors.lastname: Cukier
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Dueker
authors.forename: Susan H
authors.initials: SH
authors.lastname: Slifer
authors.forename: Joycelyn M
authors.initials: JM
authors.lastname: Lee
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Whitehead
authors.forename: Eminisha
authors.initials: E
authors.lastname: Lalanne
authors.forename: Natalia
authors.initials: N
authors.lastname: Leyva
authors.forename: Ioanna
authors.initials: I
authors.lastname: Konidari
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Gentry
authors.forename: William F
authors.initials: WF
authors.lastname: Hulme
authors.forename: Derek Van
authors.initials: DV
authors.lastname: Booven
authors.forename: Vera
authors.initials: V
authors.lastname: Mayo
authors.forename: Natalia K
authors.initials: NK
authors.lastname: Hofmann
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schmidt
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cuccaro
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.affiliation: John P, Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, BRB-314 (M860), Miami, FL, USA. mpericak@med.miami.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance