Rare Mendelian Variants as Hidden Contributors to Familial Multiple Sclerosis
Multiple sclerosis (MS) is a complex, polygenic immune-mediated disease influenced by both genetic susceptibility and environmental exposures. Despite decades of genome-wide association studies identifying common risk alleles, a substantial portion of MS heritability remains unexplained. The article “Common genetic etiology between ‘multiple sclerosis-like’ single-gene disorders and familial multiple sclerosis” challenges the exclusively polygenic paradigm by exploring whether rare variants in genes responsible for Mendelian neurological disorders may also contribute to familial forms of MS.
Phenotypic Overlap Between MS and Monogenic Neurological Disorders
A growing number of single-gene disorders—particularly leukodystrophies, mitochondrial diseases, and lysosomal storage disorders—present with clinical and radiological features that closely resemble MS. These include white matter lesions, progressive neurological disability, and inflammatory signatures on neuroimaging. The authors hypothesized that this phenotypic convergence may reflect shared molecular mechanisms, rather than mere diagnostic coincidence, thereby justifying a targeted genetic investigation of MS patients.
Study Design and Genetic Strategy
To test this hypothesis, the researchers selected 28 candidate genes known to cause 24 monogenic disorders with MS-like manifestations. Exome sequencing was performed on 270 MS patients, followed by large-scale genotyping in over 2,100 MS cases and 830 healthy controls. Importantly, the study emphasized familial segregation analysis, allowing the identification of rare variants that co-segregate with disease across multiple affected relatives—an approach particularly suited to uncovering high-impact mutations with reduced penetrance.
Identification of Rare Variants Segregating with Disease
This comprehensive analysis revealed nine rare coding variants across six genes—CYP27A1, LYST, PDHA1, CLCN2, GALC, and POLG—that segregated with disease in 13 multi-incident families. Notably, these variants were absent in healthy controls and often occurred in evolutionarily conserved regions, supporting their potential functional relevance. While not all variants demonstrated complete penetrance, their enrichment within affected families suggests a contributory role in disease susceptibility or modification.
CYP27A1 and the Central Role of Cholesterol Metabolism
Among the identified genes, CYP27A1 emerged as particularly compelling. This gene encodes sterol 27-hydroxylase, a key enzyme in cholesterol and oxysterol metabolism. One variant identified, p.R405W, is a known pathogenic mutation for cerebrotendinous xanthomatosis when present in a homozygous state. Its presence in heterozygous form among multiple MS patients supports the notion that partial disruption of cholesterol metabolism may predispose individuals to inflammatory demyelinating disease, especially progressive MS phenotypes.
Expanding the Spectrum of Mendelian Gene Effects
Variants in LYST and PDHA1 further reinforced the study’s central thesis. LYST mutations are classically associated with Chediak–Higashi syndrome, while PDHA1 mutations cause pyruvate dehydrogenase deficiency—both severe pediatric disorders. The identification of heterozygous missense variants in adult MS patients suggests a broader phenotypic spectrum than previously recognized, in which partial loss of function may manifest as late-onset, MS-like neuroinflammation rather than classical monogenic disease.
Implications for MS Pathogenesis and Precision Medicine
Collectively, this study provides strong evidence that rare, high-impact variants in genes traditionally associated with Mendelian disorders can contribute to familial MS. These findings highlight the genetic heterogeneity of MS and underscore the importance of integrating rare variant analysis into MS genetics. From a clinical perspective, such insights may pave the way for precision medicine approaches, where metabolic or mitochondrial pathways—rather than immune modulation alone—become therapeutic targets for selected patient subsets.
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:
Traboulsee, A.L., Sadovnick, A.D., Encarnacion, M. et al. Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Hum Genet 136, 705–714 (2017). https://doi.org/10.1007/s00439-017-1784-9
