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Disruption of neurexin 1 associated with autism spectrum disorder.

Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.

Pubmed ID: 18179900


  • Kim HG
  • Kishikawa S
  • Higgins AW
  • Seong IS
  • Donovan DJ
  • Shen Y
  • Lally E
  • Weiss LA
  • Najm J
  • Kutsche K
  • Descartes M
  • Holt L
  • Braddock S
  • Troxell R
  • Kaplan L
  • Volkmar F
  • Klin A
  • Tsatsanis K
  • Harris DJ
  • Noens I
  • Pauls DL
  • Daly MJ
  • MacDonald ME
  • Morton CC
  • Quade BJ
  • Gusella JF


American journal of human genetics

Publication Data

January 8, 2008

Associated Grants

  • Agency: NIMH NIH HHS, Id: MH64547
  • Agency: NIGMS NIH HHS, Id: P01-GM061354
  • Agency: NICHD NIH HHS, Id: P01-HD00300838
  • Agency: NINDS NIH HHS, Id: R01-NS16648
  • Agency: NICHD NIH HHS, Id: U19-HD35482

Mesh Terms

  • Autistic Disorder
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 2
  • Genetic Predisposition to Disease
  • Glycoproteins
  • Humans
  • Mutation, Missense
  • Neuropeptides
  • Protein Structure, Tertiary
  • Sequence Analysis, DNA