Exploring Novel HLA-DRB1 Variants in Familial Multiple Sclerosis: A Saudi Case Report

Multiple sclerosis (MS) is a immune-mediated neurodegenerative disease with a complex interplay of genetic and environmental factors. Although most cases are sporadic, familial MS—where multiple first- to third-degree relatives are affected—represents about 12.6% of all cases worldwide. Familial MS has been a subject of growing interest, particularly in identifying novel genetic variants contributing to disease onset and progression. A recent case report from Saudi Arabia presents new insights into familial MS, identifying two novel heterozygous variants in the HLA-DRB1 gene, which could significantly impact our understanding of MS genetics, particularly in the Middle East​.

Early Onset and Familial MS in a Saudi Family
The study focuses on a 25-year-old woman diagnosed with relapsing-remitting MS (RRMS) at the early age of 13. RRMS is characterized by relapses followed by periods of remission, and it is the most common form of MS. The patient had multiple attacks involving sensory, motor, and spinal cord regions, with magnetic resonance imaging (MRI) confirming classical demyelinating lesions typical of MS​. Over the years, her disease progressed despite adhering to standard treatment with interferon beta-1a (IFNβ-1a), prompting a shift in her therapeutic regimen.

Interestingly, the patient had a strong family history of MS, with both her sister and brother also diagnosed with RRMS at relatively young ages (28 and 17, respectively). The familial clustering of MS in this family strongly suggested a potential genetic predisposition. To explore this, the researchers performed whole-genome sequencing using next-generation sequencing technologies, which revealed two previously unreported variants in HLA-DRB1​.

Novel Variants in HLA-DRB1
HLA-DRB1, part of the human leukocyte antigen (HLA) class II region on chromosome 6p21, is one of the most well-established genetic contributors to MS susceptibility across different populations. In this Saudi family, two heterozygous variants were identified: a stop variant in exon 2 (c.115C>T; p.Gln39Ter) and a missense variant in exon 5 (c.785C>G; p.Thr262Arg). The stop variant leads to protein truncation, which likely disrupts the normal function of the HLA-DRB1 protein, while the missense variant introduces a significant biochemical difference between threonine and arginine, possibly altering protein structure and function​.

These variants were absent in global databases like the 1000 Genomes Project, suggesting they might be unique to this family or region. Moreover, mutations in HLA-DRB1 are known to increase MS susceptibility (OMIM #126200), strengthening the hypothesis that these novel variants contribute to the familial form of the disease observed in this case​.

Therapeutic Response: Interferon Failure and Fingolimod Success
A striking finding in this report is the family's poor response to interferon therapy. Despite years of treatment with IFNβ-1a, the proband and her siblings continued to experience relapses and disease progression. This aligns with previous reports that suggest familial MS patients may respond differently to standard disease-modifying therapies (DMTs) compared to sporadic cases​.

In contrast, all three siblings showed remarkable improvement after switching to fingolimod, an oral DMT that modulates sphingosine-1-phosphate receptors to reduce lymphocyte migration into the central nervous system. Fingolimod treatment resulted in a significant reduction in relapse rates and improved MRI outcomes, particularly in terms of lesion progression and cerebellar atrophy​. This case emphasizes the need for personalized treatment strategies in familial MS, where certain genetic variants might influence therapeutic outcomes.

Genetic Testing in Familial MS: Clinical Implications
This report highlights the importance of genetic testing in MS, particularly in familial cases. While whole-genome sequencing is still primarily a research tool, its clinical applications are growing. Identifying genetic variants like those in HLA-DRB1 can inform treatment decisions, as seen in this family, where genetic insights guided the successful switch to fingolimod​.

Moreover, genetic testing provides valuable prognostic information, helping to counsel patients and their families about disease course and therapeutic expectations. For instance, early detection of pathogenic variants could lead to earlier interventions and better long-term outcomes.

Conclusion: Expanding the Genetic Spectrum of MS
This case from Saudi Arabia underscores the critical role of HLA-DRB1 variants in familial MS and the potential for genetic testing to enhance therapeutic outcomes. The discovery of these novel variants broadens the genetic spectrum of MS, particularly in Middle Eastern populations, where familial MS appears to have unique characteristics.

Further large-scale studies are needed to explore the prevalence of such variants in other families and populations, as well as their impact on treatment responses. As personalized medicine continues to evolve, integrating genetic insights into MS management could lead to more effective and tailored treatment approaches, particularly for familial cases​.

References:
Algahtani, H., Shirah, B., Khafaji, R., & Algahtani, S. (2022). Novel Heterozygous Variants in the HLA-DRB1 Gene in a Saudi Family With Early-Onset Familial Multiple Sclerosis: Therapeutic Failure and Success. International Journal of MS Care, 24(3), 100-103.