Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.
Jeongyeon Hwang, Ayuko Iverson, Amy Woroch et al.
✦ AI-curated · Sources linked
Case in brief
Two patients with the NOTCH3 p.Arg1231Cys variant presented with early-onset dementia, strokes, and extensive leukoencephalopathy. Despite the variant being classified as low-risk, both cases exhibited significant neurological symptoms, suggesting that additional factors may influence the penetrance of this mutation. The clinical course emphasizes the importance of thorough evaluation in patients with hereditary small vessel disease.
Diagnostic / clinical pearl
Clinicians should consider that even low-risk NOTCH3 variants like p.Arg1231Cys can lead to severe neurological manifestations, warranting careful assessment and monitoring.
Why it matters
Understanding the variable penetrance of genetic variants can enhance the clinical utility of genetic testing and inform management strategies in hereditary small vessel disease.