title: Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.
abstract: Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
authors.affiliation: Division of Genetics, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Chahrour
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Lim
authors.forename: Bulent
authors.initials: B
authors.lastname: Ataman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Coulter
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Christine R
authors.initials: CR
authors.lastname: Stevens
authors.forename: Christian R
authors.initials: CR
authors.lastname: Schubert
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D033922:Clathrin Heavy Chains / Q000235:genetics; D005091:Exons / Q000235:genetics; D005808:Genes, Recessive; D015894:Genome, Human; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101272:CLTCL1 protein, human; D051741:Kruppel-Like Transcription Factors; C078332:Nck protein; D015513:Oncogene Proteins; C500914:ZNF18 protein, human; D033922:Clathrin Heavy Chains; C482647:UBE3B protein, human; D044767:Ubiquitin-Protein Ligases