Our study aimed to discover novel, rare variants associated with the risk of familial multiple sclerosis (MS) in a cohort of 45 multi-affected families.

Multiply affected families, characterized by a high degree of consanguinity, have offered unique advantages in search of novel variants. 

Among these tools, famFHAT emerged as the most robust and reliable tool, revealing significant findings at a stringent p-value threshold of <0.001. Notably, two genes, UMODL1 and ATXN3, drew our attention due to their roles in MS phenotypes, which were supported by functional evidence, mouse models, and expression patterns in the literature. UMODL1 is involved in extracellular matrix and neutrophil migration, and ATXN3 is associated with the innate immune system pathway. To further investigate the highlighted genes, we conducted segregation analysis in 45 families using the full-likelihood Bayes factor (FLB) algorithm, following ACMG guidelines and utilizing penetrance values of 0.001, 0.6, and 0.6. Specifically, there were seven variants with a minor allele frequency cutoff of 0.02 in UMODL1, all with protein-altering consequences and absent in non-MS family members. These UMODL1 exonic variations showed segregation across nine families. Notably, the rs114358105 stop gain and the rs150611312 missense variants were observed in diverse familial patterns and among siblings, respectively.

Our study successfully identified novel, rare variants associated with familial MS, with famFHAT as the most reliable tool in our study. These findings highlighted the significance of genes, such as UMODL1 and ATXN3, in MS pathogenesis, providing insights into potential pathogenic implications in familial MS cohorts.