Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS+. To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.
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We gratefully acknowledge the resources provided by the participating AGRE families. This work was supported by the Wilson Family Research Foundation, The Seaver Autism Research Center, and Cure Autism Now. Fellowship support was provided by National Research Service Award NS10692 (JK) and the Genetics Training Program at the University of Michigan (T32 GM07544) (BM).
The AGRE Consortium:22 AGRE Scientific Advisory Board, Chairman, DH Geschwind, MD, PhD, UCLA, Los Angeles, CA, Members, M Bucan, PhD, University of Pennsylvania, Philadelphia, PA; WT Brown, MD, PhD, FACMG, NYS Institute for Basic Research in Developmental Disabilities, Long Island, NY; JD Buxbaum, PhD, Mt Sinai School of Medicine, New York; TC Gilliam, PhD, Columbia Genome Center, New York; DA Greenberg, PhD, Mt Sinai Medical Center, New York; DH Ledbetter, PhD, University of Chicago, Chicago, IL; B Miller, MD, UCSF, San Francisco, CA; SF Nelson, MD, UCLA School of Medicine, Los Angeles, CA; J Pevsner, PhD, Kennedy Krieger Institute, Baltimore, MD; JI Rotter, MD, Cedars-Sinai Medical Center, Los Angeles, CA; GD Schellenberg, PhD, University of Washington, Seattle, WA; CA Sprouse, EdD, Children's National Medical Center, Baltimore, MD; RE Tanzi, PhD, Massachusetts General Hospital, Boston, MA; KC Wilhelmsen, MD, PhD, University of California, San Francisco, CA, and AGRE Collaborator: JM Silverman, PhD, Mt Sinai Medical School, New York, NY.
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Weiss, L., Escayg, A., Kearney, J. et al. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry 8, 186–194 (2003). https://doi.org/10.1038/sj.mp.4001241
- sodium channel
- genetic susceptibility
- Chr 2
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