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De novo mutation in the Notch3 gene causing CADASIL
A Joutel1, D D Dodick, J E Parisi
1INSERM U25, Faculté de Médecine Necker-Enfants Malades, and Hopital Lariboisière, Paris, France.
Insights
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) can arise from new, non-inherited Notch3 gene mutations. This finding suggests CADASIL may be more common than previously thought, even without a family history.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic arteriopathy causing stroke and dementia.
- It is typically caused by inherited mutations in the Notch3 gene.
Observation:
- A patient presented with symptoms highly indicative of CADASIL, including migraine, stroke, and white matter abnormalities.
- However, this patient had no family history of similar conditions.
Findings:
- Genetic analysis revealed a de novo (new) heterozygous Arg182Cys mutation in the Notch3 gene.
- This mutation was not present in the patient's parents, confirming it was non-inherited.
Implications:
- CADASIL should be considered even in patients lacking a family history.
- The occurrence of de novo mutations suggests CADASIL may be underdiagnosed and potentially more prevalent than currently estimated.
Abstract:
CADASIL, an autosomal dominant arteriopathy responsible for stroke and dementia, is caused by strongly stereotyped mutations in the Notch3 gene. We report a patient with a condition strongly suggestive of CADASIL (migraine, stroke, and white matter abnormalities), except that this patient did not have any first-degree relatives with similar symptoms. This patient carried a heterozygous Arg182Cys mutation in the Notch3 gene; this mutation was absent in his two biological parents. These data demonstrate the occurrence of a de novo noninherited mutation in the Notch3 gene, which indicates that CADASIL should not be rejected in the absence of a family history. Therefore, our finding suggests that CADASIL may be more frequent than anticipated.