Rare Genetic Variants May Help Explain Familial Multiple Sclerosis Risk
The article investigates an important unresolved question in multiple sclerosis genetics: whether rare, predicted pathogenic variants contribute meaningfully to disease susceptibility, particularly in familial multiple sclerosis. Although genome-wide association studies have identified more than 200 common MS-associated loci, these variants explain only part of the expected heritable risk. The authors therefore focus on rare variants in genes already implicated by GWAS, proposing that familial MS may carry a stronger burden of rare functional variation than sporadic MS.
Why Familial Multiple Sclerosis Is Biologically Informative
Familial multiple sclerosis provides a valuable model for studying inherited susceptibility because affected individuals have at least one first-degree relative with MS. The article notes that first-degree relatives of MS patients have a markedly elevated relative risk compared with the general population, and familial cases may differ clinically from sporadic cases in disease course and progression. This makes familial MS a particularly relevant setting for testing the rare variant hypothesis, which argues that low-frequency variants of moderate or large effect may contribute to complex disease risk.
Study Design and Cohort Structure
The study analyzed 4042 individuals of Slavic ethnic backgrounds, including 87 familial MS patients, 89 sporadic MS patients, and 3866 controls. MS patients were diagnosed according to McDonald criteria, while controls were ethnically matched and older than 40 years. Whole exome sequencing was performed on blood-derived DNA, with variant calling and annotation conducted using standard genomic tools including Burrows-Wheeler Aligner, GATK, Ensembl Variant Effect Predictor, LOFTEE, CADD, and gnomAD.
Defining Rare, Predicted Pathogenic Variants
The authors selected 111 autosomal protein-coding genes from previously reported MS GWAS loci, including genes inside and outside the extended MHC region. They excluded synonymous variants and retained rare variants with allele frequency below 1%, including variants absent from gnomAD. Variants were classified as predicted pathogenic when they were loss-of-function changes or missense variants supported by multiple deleteriousness prediction algorithms and a CADD score of at least 20. This stringent filtering strategy was designed to enrich for variants most likely to alter gene function.
Principal Findings: A Strong Signal in Familial MS
The central result is that rare, predicted pathogenic variants were significantly overrepresented in the familial MS cohort compared with controls, whereas no comparable enrichment was observed in the sporadic MS cohort. The combined MS group also showed significant enrichment, but the authors interpret the familial MS group as the primary driver of this signal. On page 3, the workflow diagram summarizes the study design, moving from cohort selection and whole exome sequencing to GWAS-gene filtering, panel burden analysis, and gene-level rare variant burden testing.
Candidate Genes and Biological Interpretation
Six genes showed significant rare variant burden in familial MS: ALPK2, ANKRD55, INTS8, IQCB1, JADE2, and MALT1. These genes are biologically plausible candidates because they intersect with immune regulation, inflammation, neurodevelopment, or cellular signaling. MALT1 is especially notable because it participates in lymphocyte activation, NF-κB signaling, and inflammatory gene expression, all of which are relevant to MS immunopathology. The table on page 3 lists the burdened genes, variant counts across cohorts, and FDR-adjusted p-values, emphasizing the contrast between familial and sporadic MS.
Significance, Limitations, and Future Directions
This study supports the view that rare pathogenic variation in GWAS-associated genes may contribute specifically to familial MS susceptibility. However, the authors acknowledge important limitations, including the absence of segregation analysis because only one affected individual per family was included, the relatively small number of MS cases, possible effects of common variants in linkage disequilibrium, and the lack of functional validation. Future studies with larger familial cohorts, family-based sequencing, transcriptomic integration, and experimental assays will be essential to determine whether these rare variants directly alter immune or neurological pathways involved in MS pathogenesis.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Turk, A., Maver, A., Juvan, P. et al. Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis. Sci Rep 15, 21200 (2025). https://doi.org/10.1038/s41598-025-04741-7
