Pathogenic Variants of Monogenic Stroke More Frequent in General Population

The presence of rare pathogenic variants of monogenic stroke in the general population is more common than expected.

Rare pathogenic variants associated with monogenic stroke are more prevalent in the general population than previously expected, according to study findings published in JAMA Neurology.

Rare variants in notch receptor 3 (NOTCH3), HtrA serine peptidase 1 (HTRA1), and collagen type IV alpha 1 chain (COL4A1) and 2 chain (COL4A2) have been associated with subcortical infarct or small vessel stroke and intracerebral hemorrhage. Recent studies have reported a prevalence of 1 in 452 and 1 in 275 for these NOTCH3 and HTRA1 variants, respectively.

Researchers conducted a multicenter, population-based study, researchers to determine the frequency and associated risk for these variants using a large genetic sample. Data were sourced from the UK Biobank which comprised 454,756 individuals who were recruited in the United Kingdom between 2006 and 2010. A subset of 100,000 individuals who lived in close proximity to an imaging center underwent magnetic resonance imaging (MRI). Instances of stroke and dementia were assessed through 2021 and related with rare variant carriage.

The study population included 45.8% men and the average age of participants was 56.5 (standard deviation [SD], 8.1) years.

Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants.

For NOTCH3, 973 individuals were heterozygous carriers of 99 unique NOTCH3 variants, the most common of which were p.Arg1231Cys (n=255) and p.Cys1222Gly (n=212). For HTRA1, 546 heterozygous carriers of 18 unique variants were observed. The most common HTRA1 variant was p.Ag227Trp (n=379). For COL4A1/2, 336 heterozygous carrier of 11 unique variants were observed, the most common of which was p.Gly332Arg (n=174).

Carrying a NOTCH3 variant was associated with increased risk for:

  • vascular dementia (odds ratio [OR], 5.42),
  • ischemic stroke (OR, 2.65),
  • intracerebral hemorrhage (OR, 2.42),
  • all-cause dementia (OR, 2.26),
  • any stroke (OR, 2.16),
  • epilepsy (OR, 1.72), and
  • family history of stroke (OR, 1.50).

Carriers of a HTRA1 variant were at increased risk for:

  • migraine with aura (OR, 10.36),
  • all-cause dementia (OR, 2.17),
  • ischemic stroke (OR, 2.01),
  • any stroke (OR, 1.86), and
  • family history of stroke (OR, 1.36).

The COL4A1/2 variants were assoicated with intracerebral hemorrhage (OR, 3.56) and all stroke (OR, 1.67) risk.

During follow-up, NOTCH3 was associated with risk for incident stroke (hazard ratio [HR], 2.60) and vascular dementia (HR, 5.74). Meanwhile, HTRA1 variants were linked with incident stroke (HR, 1.80). In general, individuals with higher Framingham cardiovascular risk scores (FRS) were at increased risk for ischemic stroke, however, an additive interaction was observed between FRS and NOTCH3 (synergy index [SI], 1.66) and HTRA1 (SI, 1.60) variants.

During MRI, the NOTCH3 carriers and HTRA1 carriers differed from noncarriers in peak width skeletonized mean diffusivity (both P <.001), white matter hyperintensities volume (both P <.001), global efficiency of structural brain network (both P ≤.01), and local efficiency of structural brain network (both P ≤.01); and NOTCH3 carriers also differed from noncarriers for brain volume (P =.01).

This study may have been limited by relying on medical coding for diagnoses, which can be misclassified for some conditions, especially in the case of dementia.

“Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD [cerebral small vessel disease] variants,” the researchers stated. They concluded that “This lays the foundation for future studies to evaluate the effect of early identification before symptom onset on mitigating stroke and dementia risk.”

Additional study is needed to focus on whether reducing vascular risk factors may mitigate some of the risk associated with these rare variants.

This article originally appeared on Neurology Advisor


Cho BPH, Harshfield EL, Al-Thani M, Tozer DJ, Bell S, Markus HS. Association of vascular risk factors and genetic factors with penetrance of variants causing monogenic stroke. JAMA Neurol. Published online October 27, 2022. doi:10.1001/jamaneurol.2022.3832