Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.

Jeongyeon Hwang; Ayuko Iverson; Amy Woroch; Ophir Keret; Fanny M Elahi; Georges Naasan

doi:10.1007/s10048-026-00937-9

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Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.

Jeongyeon Hwang·Ayuko Iverson·Amy Woroch·Ophir Keret·Fanny M Elahi·Georges Naasan

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Abstract

Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.

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Humans CADASIL Mutation, Missense Penetrance Receptor, Notch3 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)Cys-altering NOTCH3 variants Variable penetrance p.Arg1231Cys variant Journal Article Case Reports

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Jeongyeon Hwang, Ayuko Iverson, Amy Woroch, Ophir Keret, Fanny M Elahi, Georges Naasan. 2026-09-02. Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.. https://doi.org/10.1007/s10048-026-00937-9

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