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Condition report · Neurological

Multiple Sclerosis

Whole genome sequencing determines HLA haplotypes (DRB1*15:01 and 200+ additional MS-associated variants) and evaluates monogenic MS mimics such as LMNB1, CSF1R, HTRA1 (CARASIL), and NOTCH3 (CADASIL). This distinguishes true MS from treatable genetic leukodystrophies.

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About this condition

A progressive autoimmune disorder affecting the central nervous system resulting in demyelination. Patients develop physical and cognitive impairments that correspond with the affected nerve fibers.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system affecting approximately 1 million people in the US. MS heritability is approximately 50%, with the HLA-DRB1*15:01 allele as the strongest single genetic risk factor, carrying approximately 3-fold increased risk. Over 230 common genetic variants have been identified through GWAS, collectively explaining approximately 48% of the genetic risk. Additional susceptibility genes include IL7R, IL2RA, CD58, TNFRSF1A, and IRF8.

While MS is polygenic in most patients, the most clinically important application of genetic testing in MS is the identification of rare monogenic diseases that mimic MS clinically and radiologically but have fundamentally different etiologies and treatments. CADASIL (NOTCH3) presents with white matter lesions, cognitive decline, and migraine, often misdiagnosed as MS for years. CARASIL (HTRA1) presents similarly with additional alopecia. Adult-onset leukodystrophies (LMNB1: autosomal dominant adult-onset leukodystrophy; CSF1R: adult-onset leukoencephalopathy with axonal spheroids) produce progressive white matter disease indistinguishable from progressive MS on MRI.

Patients diagnosed with 'MS' who carry a monogenic white matter disease variant do NOT respond to MS disease-modifying therapies (interferon-β, natalizumab, ocrelizumab), because their disease is not autoimmune demyelination. Continued treatment with MS therapies (which carry significant side effects including PML risk with natalizumab) without benefit is harmful. Genetic testing identifies these patients, redirecting them to appropriate management. Additionally, HLA-DRB1*15:01 status may influence MS therapy selection in future precision medicine approaches.

Monogenic MS mimics (CADASIL, CARASIL, CSF1R leukodystrophy) do NOT respond to MS therapies. Patients misdiagnosed as MS receive immunosuppressive treatments with serious risks but no benefit. Genetic testing prevents ongoing iatrogenic harm.

The condition we analyse

A progressive autoimmune disorder affecting the central nervous system resulting in demyelination. Patients develop physical and cognitive impairments that correspond with the affected nerve fibers.

What a diagnosis changes

MS: disease-modifying therapies (ocrelizumab, natalizumab, fingolimod, dimethyl fumarate); CADASIL: antiplatelet therapy, migraine management, cognitive support; CSF1R leukodystrophy: HSCT (emerging); genetic counseling for monogenic mimics

Also known as

generalised multiple sclerosis; generalized multiple sclerosis

Includes 7 related subtypes ↓
  • chronic progressive multiple sclerosis
  • Marburg acute multiple sclerosis
  • pediatric multiple sclerosis
  • primary progressive multiple sclerosis
  • progressive relapsing multiple sclerosis
  • relapsing-remitting multiple sclerosis
  • secondary progressive multiple sclerosis
MONDO:0005301Orphanet 802MedGen 10123

Why whole genome sequencing

The primary clinical utility of genetic testing in MS is identifying the ~3-5% of 'MS' patients who actually have a genetic leukodystrophy or vasculopathy, changing treatment from harmful immunosuppression to appropriate disease-specific management.

CADASIL is misdiagnosed as MS in up to 10% of cases: years of ineffective MS therapy while the true diagnosis goes untreated

CADASIL (NOTCH3) produces periventricular and subcortical white matter lesions on MRI that can satisfy the McDonald diagnostic criteria for MS. Patients may receive MS disease-modifying therapies for years without benefit, while the CADASIL progresses with cognitive decline, recurrent strokes, and vascular dementia. NOTCH3 testing should be considered in any 'MS' patient with atypical features: prominent migraine with aura, subcortical infarcts, cognitive decline disproportionate to clinical disability, or family history of stroke/dementia. WGS identifies NOTCH3 variants alongside HLA typing and evaluation of all other white matter disease genes.

HLA-DRB1*15:01 typing may guide future precision MS therapy selection, establishing baseline genetic architecture for emerging stratified approaches

While HLA-DRB1*15:01 status does not currently change MS therapy selection, precision medicine approaches in MS are emerging. Studies suggest that HLA-DRB1*15:01 carriers may respond differently to specific disease-modifying therapies. Genome-wide polygenic risk scores for MS are in development for clinical use. Establishing a patient's complete genetic architecture through WGS provides a permanent resource for ongoing reanalysis as pharmacogenomic MS research matures, without requiring repeat testing.

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