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Neurology. 2012 Jul 31;79(5):406-11. doi: 10.1212/WNL.0b013e3182616fc4. Epub 2012 Jun 27.

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

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  • 1The Department of Medical Genetics, University of Ottawa, Ottawa, Canada.



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.


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.


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).


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.

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