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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.

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.

Comment in

PMID:
22744673
[PubMed - indexed for MEDLINE]
PMCID:
PMC3405256
Free PMC Article

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