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. 2021 Jul 15:12:705284.
doi: 10.3389/fgene.2021.705284. eCollection 2021.

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Yacen Hu  1   2 , Qiying Sun  1   2 , Yafang Zhou  1   2 , Fang Yi  1   2 , Haiyun Tang  3 , Lingyan Yao  1   2 , Yun Tian  1   2 , Nina Xie  1   2 , Mengchuan Luo  1   2 , Zhiqin Wang  1   2 , Xinxin Liao  1   2 , Hongwei Xu  1   2 , Lin Zhou  1   2
Affiliations

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Yacen Hu et al. Front Genet. .

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.

Keywords: CADASIL; Notch3; cysteine-sparing variant; genotype-phenotype; untypical variant.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Exon distribution of the cysteine-affecting and cystine-sparing NOTCH3 variants identified in 38 patients. (B) Pie chart displaying the proportion of patients carrying cystine-affecting variants and cystine-sparing variants. (C) Pie chart displaying the proportion of patients carrying NOTCH3 variants within EGFr region and outside EGFr region.
FIGURE 2
FIGURE 2
Family pedigrees of patients carrying untypical NOTCH3 variants. The arrow points to the proband. Square and circles indicate males and females, respectively. A bar across the symbol means a decreased individual. Symptomatic family members are shown in black filled. Asymptomatic family members with MRI abnormalities are shown in stripe filled. Asterisks indicate gene-tested subjects. WT, wide type; mt, mutant variant.
FIGURE 3
FIGURE 3
Magnetic resonance images in three patients carrying novel NOTCH3 variants outside EGFr coding region. Fluid-attenuated inversion recovery images of the carrier of S2203Y (A–C), V1922L (D–F), and R1761H (G,H) showing multiple subcortical lacunar infarcts and characteristic diffuse leukoaraiosis with involvement of the external capsule. SWI images showed multiple microbleeds in basal ganglion and subcortical region of the carrier of R1761H (I).
FIGURE 4
FIGURE 4
Representative images of skin biopsies. Electron microscopy of skin biopsies from the proband carrying R133S (A) and R607H (B), showing deposits of GOM (black arrow).
FIGURE 5
FIGURE 5
Patient enrollment and study work flow. PV, pathogenic variant; VUS, variant of unknown significance.
See this image and copyright information in PMC

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