NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients.

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

doi:10.3389/fgene.2021.705284

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.

Highlights

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM NO.125310) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene (Joutel et al, 1996)
We investigated the spectrum of NOTCH3 variants in Chinese CADASIL patients by sequencing all coding exons of NOTCH3
Skin biopsies were performed in 13 proband patients carrying NOTCH3 variants, and granular osmiophilic material (GOM) was detected in 11 proband patients (11/13, 84.62%)

Summary

Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM NO.125310) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene (Joutel et al, 1996). Deposition of Notch extracellular domain or granular osmiophilic material (GOM) in small arteries is a pathological hallmark of CADASIL (Joutel et al, 2000). The NOTCH3 gene contains 33 exons encoding the Notch protein, a single-pass transmembrane receptor of 2,321 amino acids. Notch contains a large extracellular domain (ECD) that consists of 34 epidermal growth factor-like repeats (EGFr), a transmembrane domain (TMD), and an intracellular domain (ICD) (Wang et al, 2008). More than 300 NOTCH3 mutations have been reported, and most of the pathogenic mutations reside in exons 2–24 coding for EGFr 1–34 in the ECD of the Notch protein. Most mutations are missense mutations that change the number of cysteines in EGFr, leading to misfolding of the receptor and aggregation of the extracellular domain (Rutten et al, 2014)

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