Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene.

Dyment, D; Cader, M; Chao, M; Lincoln, MR; Morrison, K; Disanto, G; Morahan, J; Luca, D; Sadovnick, A; Lepage, P; Montpetit, A; Ebers, G; Ramagopalan, S

Journal article

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene.

Abstract:: OBJECTIVE: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations. METHODS: We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families. RESULTS: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; χ(2) = 5.76, p = 0.016). CONCLUSIONS: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.

Publication status:: Published

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APA Style

Dyment, D., Cader, M., Chao, M., Lincoln, M. R., Morrison, K., Disanto, G., Morahan, J., Luca, D., Sadovnick, A., Lepage, P., Montpetit, A., Ebers, G., & Ramagopalan, S. (2012). Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene. Neurology, 79(5), 406–411.

MLA Style

Dyment, D., et al. “Exome Sequencing Identifies a Novel Multiple Sclerosis Susceptibility Variant in the TYK2 Gene.” Neurology, vol. 79, no. 5, 2012, pp. 406–11.

Chicago Style

Dyment, D, M Cader, M Chao, MR Lincoln, K Morrison, G Disanto, J Morahan, et al. 2012. “Exome Sequencing Identifies a Novel Multiple Sclerosis Susceptibility Variant in the TYK2 Gene.” Neurology 79 (5): 406–11.
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