Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism

PLoS Genet. 2012;8(4):e1002635. doi: 10.1371/journal.pgen.1002635. Epub 2012 Apr 12.


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.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Autistic Disorder / genetics*
  • Clathrin Heavy Chains / genetics
  • Exons* / genetics
  • Genes, Recessive*
  • Genome, Human
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Mutation*
  • Neurons* / metabolism
  • Neurons* / physiology
  • Oncogene Proteins / genetics
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases / genetics


  • Adaptor Proteins, Signal Transducing
  • CLTCL1 protein, human
  • Kruppel-Like Transcription Factors
  • Nck protein
  • Oncogene Proteins
  • ZNF18 protein, human
  • Clathrin Heavy Chains
  • UBE3B protein, human
  • Ubiquitin-Protein Ligases