Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants

J Neurol. 2023 Mar;270(3):1501-1511. doi: 10.1007/s00415-022-11401-7. Epub 2022 Nov 21.


Background: Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far.

Material and methods: We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center.

Results: Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry's disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%).

Conclusion: Genetic screening for Fabry's disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

Keywords: Gene panel; Ischemic stroke; Juvenile stroke; Stroke etiology; Whole-exome sequencing.

MeSH terms

  • CADASIL* / diagnostic imaging
  • CADASIL* / genetics
  • Exome
  • Fabry Disease* / genetics
  • Humans
  • Ischemic Stroke* / genetics
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation / genetics
  • Receptor, Notch3 / genetics
  • Receptors, Notch / genetics
  • Stroke* / diagnostic imaging
  • Stroke* / genetics
  • Stroke, Lacunar* / genetics


  • Receptor, Notch3
  • Receptors, Notch
  • NOTCH3 protein, human