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.
The exome is the part of the genome formed by exons, the coding portions of genes that are expressed. This provides the genetic blueprint used in the synthesis of proteins and other functional gene products, the exome is the most functionally relevant part of the genome and, therefore, the most likely to contribute to the phenotype of an organism. The exome of the human genome consists of roughly 180,000 exons constituting about 1% of the total genome but is thought to carry about 85% of disease-causing mutations.
Exome sequencing (ES), a transformative tool that targets protein coding exons using next-generation DNA sequencing (technologies that rapidly produce many thousands or millions of short reads [25-500 bp] in parallel at low cost), has revolutionized gene discovery for single gene mutation disorders. In the past 2 years, ES has identified genes for >70 single gene conditions and the pace is accelerating. ES to identify a putative risk variant for multiple sclerosis (MS) in an unusual family with 15 affected individuals, illustrating both the power of ES. However, the fact that this has been missed in other genome wide studies suggests that if you lump all MSers together then you may miss some of the causative genes, which has been found here.
If you have twenty rabbits where you can find the genetic cause in each rabbit (which is the same as looking in a special family = one rabbit as used here). Know imagine that you put these rabbits in a barn and they make thousands of different rabbits through interbreeding. It is then a very, very difficult task to find the genes that are causative. This been a problem with population-based genome studies especially when they are looking at small group size of a fraction of the population. This a current study looks at a unique family and finds rare gene variants that are associated with disease susceptibility, that would be unlikely to be located in whole population-based studies.
CoI: This study was led by Ram who is a member of Team G