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Updated: Sep 9, 2025

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Small Vessel Disease Phenotype Associated With Monoallelic NOTCH3 Loss-of-Function Variants.

Josephine S van Asbeck1, Gido Gravesteijn1, Minne N Cerfontaine1

  • 1Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

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Summary

Monoallelic NOTCH3 loss-of-function variants cause a subclinical small vessel disease, distinct from CADASIL. Disease may worsen with aging and cardiovascular risk factors, guiding future management.

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Area of Science:

  • Neurology
  • Genetics
  • Vascular Biology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 cysteine-altering variants.
  • Biallelic NOTCH3 loss-of-function variants cause a rare childhood-onset small vessel disease.
  • The role of monoallelic NOTCH3 loss-of-function variants in small vessel disease is debated.

Purpose of the Study:

  • To delineate the small vessel disease phenotype in individuals with monoallelic NOTCH3 loss-of-function variants.
  • To compare this phenotype with CADASIL.

Main Methods:

  • Observational study using gnomAD, UK Biobank, and clinical data.
  • Analysis of white matter hyperintensity volume, diffusivity, lacune count, and stroke incidence.
  • Skin vessel wall pathology assessed via immunohistochemistry and electron microscopy.

Main Results:

  • Monoallelic NOTCH3 loss-of-function cases showed increased white matter hyperintensity and diffusivity, comparable to NOTCH3 cysteine-altering variant cases.
  • Stroke risk was not elevated in monoallelic NOTCH3 loss-of-function cases compared to controls.
  • Skin vessels exhibited more collagen deposition in monoallelic NOTCH3 loss-of-function cases.

Conclusions:

  • Monoallelic NOTCH3 loss-of-function variants cause a distinct small vessel disease, often subclinical.
  • Disease presentation can be influenced by cardiovascular risk factors and age.
  • Findings aid in counseling and managing individuals with NOTCH3 loss-of-function variants.