R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.

Genotypic and phenotypic variation of CADASIL among Chinese, Indians and Rungus in Malaysia

“…However, other studies such as those in eastern and southern China, Taiwan and Korea showed a different result, with the majority being mutations in exon 11 [2][3][4]. The neuroimaging features in these studies were also different, with a lower percentage (20-45.8%) of anterior temporal pole involvement and a higher prevalence of intracranial haemorrhage [3,4,7] Previous reported genetically confirmed cases from Malaysia include a Rungus family [8] and a Chinese Malaysian family who resides in Singapore [5]. In concordance with the multiethnic diversity of the country, this case series highlights the variations in genotypes and phenotypes among various ethnic groups in Malaysia.…”

“…To have a more complete profile of a Malaysian case series, two previously reported Malaysian families were included in the analysis, consisting of a Rungus family reported by Lim et al [8] and a Malaysian Chinese family by Wilder-Smith et al [5].…”

“…The number of CADASIL cases reported in Asia is increasing [2][3][4][5][6][7][8] with better recognition of the condition and improved access to genetic testing. Few studies have compared the mutation profiles between Asians and Caucasians.…”