A recent study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of multiple sclerosis (MS). Researchers examined whole‐genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects. They selected pathogenic variants exclusively found in patients with primary progressive MS (PPMS) that cause monogenic neurologic disorders, and performed 2 rounds of replication genotyping in 746 PPMS, 3,049 relapsing MS (RMS), and 1,000 healthy subjects. To refine their findings, they examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSP) in PPMS (n=314), secondary progressive MS (SPMS) (n=587), RMS (n=2,248), and healthy subjects (n=987) genotyped using the MS replication chip. They found:

• WGS and replication studies identified 3 pathogenic variants in PPMS patients that cause neurologic disorders sharing features with MS.
• Moreover, a significant enrichment of HSP‐related mutations in PPMS patients was detected compared to controls, as well as in SPMS patients compared to controls.
• Importantly, this enrichment was not detected in RMS.