Genetics

This study investigates the genetic basis of familial multiple sclerosis in two multi-incident Iranian families using whole-exome sequencing, segregation analysis, and molecular modeling. The most significant finding is the identification of co-segregating copy number variants in BTNL3 and BTNL8, which likely generate a BTNL8*3 fusion protein with reduced binding affinity to the Vγ4 T-cell receptor, suggesting impaired γδ T-cell regulation and a possible contribution to neuroinflammation in MS. A second rare variant in MBL2 was also identified, although its incomplete segregation suggests a modifier rather than causative role. Overall, the article highlights the importance of rare structural and coding variants in familial MS and proposes a biologically plausible immune mechanism that warrants further functional validation.