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Genotype–phenotype correlations and effect of mutation location in Japanese CADASIL patients

Journal of Human Genetics volume 65, pages 637–646 (2020)Cite this article

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype–phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype–phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1–6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7–34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

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Acknowledgements

We thank all the participants and their physicians. We also thank Hiromi Yasuike for technical support on conducting genetic analysis, and eigoclinic for English language editing. This study was supported by the Japan Agency for Medical Research and Development (AMED, 17ek0109130s0703), and by a grant-in-aid for Research on Intractable Disease from the Japanese Ministry of Health, Labour, and Welfare, Japan (H28-Nanchitou(Nan)-Ippan-029, H30-Nanchitou(Nan)-Ippan-006).

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  1. Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Mao Mukai, Ikuko Mizuta, Akiko Watanabe-Hosomi, Takashi Koizumi, Jun Matsuura, Ai Hamano & Toshiki Mizuno

  2. Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan

    Hidekazu Tomimoto

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  1. Mao Mukai
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Mukai, M., Mizuta, I., Watanabe-Hosomi, A. et al. Genotype–phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet 65, 637–646 (2020). https://doi.org/10.1038/s10038-020-0751-9

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