Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3–6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.

Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study

“…In a recent report in 29 Korean mutation carriers, the exon 11 contributed the most and p.Arg544Cys were relatively common, while the ratio of mutations in exon 4 was extremely low . In our Han Chinese cohort, which contained patients largely from eastern and southern China, the exon 11 was considered to be a “hot region,” in line with previous reports . Interestingly, a recent research based on ExAC database indicated that mutations causing CADASIL revealed an obvious distribution discrepancy and predominately located outside EGFR 1‐6 .…”

“…(A) The p.Arg607Cys mutation carriers mainly locate in Shanghai, Zhejiang, and Jiangsu. (B) The p.Arg544Cys mutation carriers mainly locate in Fujian and Taiwan (Data from Lee et al and Liao et al …”

“…Studies in northern Chinese population were consistent with these findings . Nevertheless, studies conducted in another Han Chinese population revealed that mutations located in exon 11 might be more frequent in southeast China and p.Arg544Cys mutation might be a “hot spot.” Additionally, founder effect has been described in several studies of CADASIL, which might be one of the reasons leading to different mutation spectrum.…”

CADASIL: two new cases with intracerebral hemorrhage

“…Neuroimaging abnormalities such as cerebral white matter lesions (WMLs), lacunes, and microbleeds in the CADASIL patients are related to this cerebral small‐vessel histopathology 1. While CADASIL is considered a primarily ischemic form of vascular dementia, spontaneous intracerebral hemorrhage (ICH) has recently been reported in association with CADASIL,2, 3, 4, 5, 6 suggesting that the structural fragility of arterial walls may lead to ICH attacks. However, there are limited data describing the effects that the underlying structural changes related to CADASIL have on the occurrence of ICH and subsequent outcomes.…”

Koronarine Širdies Liga Sergančiųjų Smegenų Pokyčių Įvertinimas

“…Autosominiu dominantiniu būdu paveldima smegenų arteriopatija kartu su požieviniais infarktais bei leukoencefalopatija yra dažniausia kraujotakos sutrikimų sąlygojama demencijos priežastis ir yra siejama su NOTCH3 geno mutacijomis [8]. NOTCH3 genas koduoja transmembraninį baltymą, kurio raiška aptikta kraujagyslių lygiųjų raumenų ląstelių citoplazminiame tinkle [9].…”