Disruption of neurexin 1 associated with autism spectrum disorder.

Abstract

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.

DOI: 10.1016/j.ajhg.2007.09.011

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@article{Kim2008DisruptionON, title={Disruption of neurexin 1 associated with autism spectrum disorder.}, author={H R Kim and Shotaro Kishikawa and Anne W. Higgins and Ihn-Sik Seong and Diana J. Donovan and Yiping Shen and Eric Lally and Michela Traglia and J. Najm and Kerstin Kutsche and Maria Descartes and Lynn C. Holt and Stephen R . Braddock and Robin Troxell and Lee M. Kaplan and Fred Volkmar and Ami J Klin and Katherine D Tsatsanis and David J. Harris and Ilse L. J. Noens and David L. Pauls and Mark J. Daly and Marcy E. MacDonald and Cynthia C Morton and Bradley J. Quade and James F. Gusella}, journal={American journal of human genetics}, year={2008}, volume={82 1}, pages={199-207} }