rs137852641 — NOTCH3

Pathogenic NOTCH3 missense variant p.Arg332Cys that alters the cysteine count in EGF-like repeat 6, causing CADASIL — the most common inherited cause of ischemic stroke and vascular dementia

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NOTCH3 Arg332Cys — The Most Common Inherited Cause of Stroke

NOTCH3 encodes a cell-surface signalling receptor expressed almost exclusively in vascular smooth muscle cells. When NOTCH3 functions normally, it helps small arteries maintain their structure and tone throughout life. The Arg332Cys variant disrupts a cysteine in the sixth [epidermal growth factor-like (EGF-like) repeat | NOTCH3's extracellular domain is made of 34 EGF-like repeats, each stabilised by three disulfide bonds formed by six precisely-spaced cysteine residues. Odd-numbered cysteines in each repeat pair with even-numbered ones; adding or removing a cysteine breaks that pairing and causes the domain to misfold] of NOTCH3's extracellular domain — a change that, over decades, silently destroys the small arteries that supply deep brain structures. The resulting disease, [CADASIL | Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy — the name describes the anatomy: arteries (arteriopathy) supplying deep gray/white matter (subcortical) produce both small strokes (infarcts) and white matter damage (leukoencephalopathy)], is the most common inherited cause of stroke and vascular dementia in adults.

The Mechanism

NOTCH3's 34 EGF-like repeats depend on correctly paired disulfide bonds for structural integrity. Each repeat contains six cysteines that form three obligate pairs (C1-C2, C3-C4, C5-C6). The Arg332Cys substitution introduces an unpaired cysteine in repeat 6, breaking the rigid pairing rule. The [misfolded extracellular domain | The monomeric NOTCH3 ECD cannot be cleared by normal proteostasis and accumulates at the vessel wall surface. This aggregate forms the pathological hallmark of CADASIL: GOM (granular osmiophilic material) deposits visible on electron microscopy of skin or brain vessel biopsies] cannot fold correctly, and the protein accumulates on the surface of smooth muscle cells rather than participating in normal signalling.

Over years of accumulation, the [smooth muscle cells | The principal cellular target in CADASIL — smooth muscle cells in small penetrating arteries degenerate and are replaced by fibrosis, thickening the vessel wall and reducing the lumen. The result is chronic hypoperfusion and vulnerability to small infarcts in territory the arteries supply: deep white matter, basal ganglia, thalamus, brainstem] progressively degenerate and are replaced by fibrosis. The small penetrating arteries supplying deep brain structures — the lenticulostriate arteries, thalamic perforators, brainstem perforators — narrow and stiffen, eventually causing lacunar infarcts and the characteristic white matter hyperintensities visible on FLAIR MRI. Because NOTCH3 is expressed almost exclusively in smooth muscle cells (not endothelium or neurons), the pathology is pure vasculopathy: neurons die not from a primary genetic defect but from the vascular failure upstream.

The Arg332Cys variant is located in exon 6 — a [less common mutation site for CADASIL | The majority of CADASIL mutations cluster in exons 3-4 (EGF-like repeats 1-5). Exon 6 mutations are rarer and may carry slightly different phenotypic features, including a lower rate of anterior temporal lobe involvement and possible lower penetrance in some families], contrasting with the more common exon 3-4 hotspot. Regardless of the exact exon location, any cysteine-altering NOTCH3 mutation is classified as pathogenic by the diagnostic criterion [defined by Rutten et al. | 2014, Expert Rev Mol Diagn, PMID 24844136]: gain or loss of a cysteine residue in any of the 34 EGF-like repeats.

The Evidence

A landmark UK Biobank analysis of 200,632 participants by Cho et al.11 landmark UK Biobank analysis of 200,632 participants by Cho et al.
J Neurol Neurosurg Psychiatry 2021 found cysteine-altering NOTCH3 variants in approximately 1 in 450 individuals in the general population — far more than the 1 in 15,000 estimated from classic CADASIL clinical case series, suggesting profound underdiagnosis. Carriers had a 2.33-fold increased stroke risk (p=0.0004), a 5-fold increased vascular dementia risk (p=0.007), significantly greater white matter hyperintensity volume, elevated lacune burden (5.97-fold increase), and increased cerebral microbleeds (4.38-fold increase) — the full neuroimaging signature of CADASIL, present in individuals who had never received a clinical diagnosis.

Phenotypic data specific to Arg332Cys comes from case series. Li et al. 202022 Li et al. 2020
Annals of Translational Medicine characterized 12 published Arg332Cys cases with a mean symptom onset age of 37.8 ± 9.4 years, earlier than the 47-year average across all CADASIL mutations per GeneReviews. Stroke or TIA was the presenting event in 83.3%, cognitive decline in 58.3%, and psychiatric disturbance in 50%. Sano et al. 201133 Sano et al. 2011
Internal Medicine documented phenotypic heterogeneity even within families carrying identical Arg332Cys mutations: one proband presented with syncope only, another with recurrent ischemic events followed by intracranial hemorrhage — illustrating that clinical course is not precisely predictable from the genotype alone.

No proven disease-modifying therapy exists for CADASIL. Thrombolytic therapy and oral anticoagulants [probably increase intracerebral hemorrhage risk | GeneReviews CADASIL: cerebral microbleeds, present in 31-69% of CADASIL patients, represent fragile small vessels at high bleeding risk; anticoagulants that would normally benefit embolic stroke are counterproductive here] and are generally avoided. Antiplatelet therapy may reduce ischemic event risk and is widely used in practice, though randomized trial evidence is lacking. Blood pressure control is a clear priority: faster disease progression is documented in individuals with elevated systolic blood pressure.

Practical Actions

The central management goals for Arg332Cys carriers are: (1) secure a neurology referral and establish baseline MRI before symptoms appear, (2) control all modifiable vascular risk factors aggressively — especially blood pressure and smoking — because these accelerate an already progressive disease, (3) avoid iatrogenic hemorrhage from thrombolytics or anticoagulants in the acute stroke setting, and (4) enable cascade family testing so other carriers are identified before their first infarct.

Migraine with aura, present in 30-75% of CADASIL patients across mutations, is often the earliest symptom. Triptans have been used safely in CADASIL patients in published series without documented vascular complications, though the evidence base is observational. Standard migraine prophylaxis (beta-blockers, topiramate, valproate) follows general guidelines.

Pregnancy carries a modestly elevated risk of neurological events, particularly in the peripartum period. Maternal-fetal medicine consultation is recommended before conception. Antiplatelet therapy in pregnancy should be individualized with specialist input.

Interactions

No single-variant gene-gene compound action is specifically documented for rs137852641, but the broader CADASIL phenotype interacts strongly with modifiable vascular risk factors. Carriers who also have hypertension-amplifying variants (AGT, ACE), dyslipidaemia variants (APOE4, LDLR), or pro-inflammatory variants (IL-6, CRP) may have accelerated white matter lesion progression — though the interaction evidence is observational rather than established from controlled genetic studies.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No NOTCH3 Arg332Cys — normal CADASIL risk for this variant

You carry two copies of the reference G allele at rs137852641. Your NOTCH3 gene at this position produces arginine at protein position 332, preserving the correct cysteine count in EGF-like repeat 6. You do not carry the Arg332Cys CADASIL-causing mutation. This is the genotype found in essentially the entire global population — the A allele has a frequency of approximately 2 in 1.4 million chromosomes in gnomAD.

AG CADASIL Carrier High Risk

One copy of Arg332Cys — pathogenic NOTCH3 variant causing CADASIL

NOTCH3 is expressed almost exclusively in vascular smooth muscle cells. The 34 EGF-like repeat domains of its extracellular domain require precisely positioned disulfide bonds for structural integrity. Each repeat contains exactly six cysteines — the Arg332Cys change adds an unpaired seventh cysteine to repeat 6, and the resulting misfold causes protein to accumulate on smooth muscle cell surfaces rather than participating in normal signalling. Over years of accumulation, smooth muscle cells degenerate, vessel walls thicken and stiffen, and the lumen of penetrating arteries narrows. Chronic hypoperfusion and susceptibility to lacunar infarcts follow.

The pathological hallmark — GOM (granular osmiophilic material) deposits — is visible on skin or brain vessel biopsy by electron microscopy, and skin biopsy with NOTCH3 immunostaining can confirm the diagnosis in clinically suspected cases without brain biopsy.

The classic CADASIL MRI signature includes: white matter hyperintensities (especially anterior temporal lobes and external capsules), subcortical lacunar infarcts, and cerebral microbleeds. These findings may appear a decade or more before clinical symptoms, making baseline neuroimaging in confirmed carriers valuable for establishing reference and monitoring progression.

Disease progression is significantly faster in individuals with elevated blood pressure and in smokers. No disease-modifying treatment has proven efficacy in clinical trials, though antiplatelet therapy is widely used for ischemic event prevention. Thrombolytics and oral anticoagulants are generally contraindicated due to the high prevalence of cerebral microbleeds (31-69% of CADASIL patients) that raise intracerebral hemorrhage risk.

Arg332Cys is located in exon 6, a less common CADASIL mutation site. Published case series have documented variable phenotypes: some carriers present with migraine with aura years before any ischemic event; others present directly with stroke or cognitive decline. Phenotypic variation exists even within the same family carrying identical mutations.

AA Homozygous CADASIL High Risk

Two copies of Arg332Cys — homozygous NOTCH3 CADASIL mutation, essentially not observed in population databases

You carry two copies of the Arg332Cys pathogenic NOTCH3 variant. The A allele has a global frequency of approximately 2 in 1.4 million chromosomes (gnomAD exomes), making homozygosity for this variant essentially absent from documented cases. If confirmed, this would represent an extraordinarily rare genotype. Homozygous CADASIL would be expected to produce severe and early-onset disease, though the precise phenotype has not been characterised in the literature. Urgent specialist evaluation is required to confirm the result and plan management.