Genetics

This blog post examines a whole-exome sequencing study investigating whether rare predicted pathogenic (RPP) variants within established multiple sclerosis (MS) GWAS-associated genes differentially contribute to familial versus sporadic disease. Using a curated panel of 111 autosomal GWAS-nominated genes and burden-testing against a large ancestry-matched control cohort, the article reports a pronounced enrichment of rare deleterious variation in familial MS but not in sporadic MS, with gene-level signals implicating ALPK2, ANKRD55, INTS8, IQCB1, JADE2, and MALT1 in familial cases and LIMK2 in sporadic cases. The post contextualizes these findings within MS genetic architecture, highlights biological plausibility for the implicated pathways, and discusses limitations and next-step research directions for integrating rare-variant burden with polygenic risk and functional validation.