Rare Genetic Variants and Familial Multiple Sclerosis: New Insights from Exome Sequencing

The article “Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis”, published in Scientific Reports in 2025, investigates an important unresolved question in multiple sclerosis genetics: whether rare, potentially damaging variants contribute disproportionately to familial multiple sclerosis. Multiple sclerosis is a chronic immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. Although genome-wide association studies have identified more than 200 common genetic risk loci for the disease, these variants explain only part of the expected heritable component. The authors therefore focus on rare variants, which may have stronger biological effects than common variants and may be especially relevant in families with multiple affected individuals.

Study Rationale and Central Hypothesis
The central hypothesis of the study is that rare, predicted pathogenic variants in genes previously associated with multiple sclerosis by GWAS are enriched in familial multiple sclerosis compared with sporadic disease and population controls. This approach is scientifically meaningful because GWAS signals usually point to common variants with modest effects, whereas familial clustering may reflect a different genetic architecture, including rare variants of larger effect. By examining rare variants within GWAS-associated genes, the authors attempt to bridge two areas of genetic research: population-level association studies and rare-variant analysis in clinically enriched patient groups.

Cohort Design and Sequencing Strategy
The study included 4042 participants of Slavic ancestry, divided into 87 familial multiple sclerosis patients, 89 sporadic multiple sclerosis patients, and 3866 control individuals. Familial cases were defined as patients with at least one first-degree relative diagnosed with multiple sclerosis, whereas sporadic cases had no first-degree relatives with the disease. Whole-exome sequencing was performed on blood-derived DNA, and variants were processed using standard genomic pipelines, including alignment to the hg38 reference genome, quality filtering, annotation with Ensembl Variant Effect Predictor, loss-of-function classification with LOFTEE, and pathogenicity scoring with CADD. This design enabled the authors to compare the burden of rare candidate variants across carefully defined clinical groups.

Variant Selection and Burden Analysis
The investigators selected 111 autosomal protein-coding genes from loci previously implicated in multiple sclerosis by the International Multiple Sclerosis Genetics Consortium. They then focused on rare variants with allele frequency below 1%, including variants absent from gnomAD, and retained only variants predicted to be pathogenic. These included high-impact variants such as frameshift, splice-site, stop-gain, stop-loss, and start-loss changes, as well as missense variants predicted deleterious by multiple algorithms and supported by a CADD score of at least 20. The statistical burden analysis was performed using a generalized linear model with false-discovery-rate correction, comparing the combined multiple sclerosis group, familial cases, and sporadic cases separately against controls.

Principal Findings: Familial MS Shows a Strong Rare-Variant Burden
The most striking result was the significant overrepresentation of rare, predicted pathogenic variants in the familial multiple sclerosis cohort, while no comparable enrichment was detected in the sporadic cohort. The combined multiple sclerosis group also showed significant enrichment, but the familial group appeared to be the major driver of this signal. The reported p-values were highly significant for familial multiple sclerosis and non-significant for sporadic multiple sclerosis, supporting the interpretation that familial disease may have a stronger rare-variant component. This finding strengthens the argument that familial and sporadic multiple sclerosis may differ, at least partly, in their genetic architecture.

Candidate Genes and Biological Interpretation
Six genes contributed significantly to the rare-variant burden in familial multiple sclerosis: ALPK2, ANKRD55, INTS8, IQCB1, JADE2, and MALT1. Several of these genes have plausible links to immune regulation, inflammation, neurodevelopment, or cellular signaling. MALT1 is particularly notable because it participates in lymphocyte activation, NF-κB signaling, and inflammatory pathways, all of which are highly relevant to multiple sclerosis pathobiology. ANKRD55 has previously been associated with autoimmune disease susceptibility, while INTS8 and JADE2 may connect genetic risk to transcriptional regulation and neural development. Although these associations do not prove causality, they identify biologically credible candidates for future functional studies.

Significance, Limitations, and Future Directions
This study provides evidence that rare, predicted pathogenic variants in GWAS-associated genes may contribute to susceptibility in familial multiple sclerosis. Its value lies in showing that genes discovered through common-variant association studies may also harbor rare variants relevant to familial disease. However, the authors acknowledge important limitations, including the inclusion of only one affected individual per family, which prevented segregation analysis, the modest size of the patient cohorts, and the absence of functional validation for the identified variants. Future studies should include larger multiethnic cohorts, sequencing of multiple affected and unaffected relatives, and experimental assays to determine whether the implicated variants alter immune or neural pathways. Overall, the article advances the field by suggesting that familial multiple sclerosis may reflect a concentrated burden of rare damaging variation within genes already implicated by broader population genetics.

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., Drulović, J., Mesaroš, Š., Novaković, I., ... & Peterlin, B. (2025). Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis. Scientific reports, 15(1), 21200.