Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3

• Published in: Journal of clinical neuroscience 2018-10, Vol.56, p.95-100
• Main Authors: Hung, Ling Yin, Ling, Tsz Ki, Lau, Nike Kwai Cheung, Cheung, Wing Lan, Chong, Yeow Kuan, Sheng, Bun, Kwok, King Ming, Mak, Chloe Miu
• Format: Article
• Language: English
• Subjects: Adult onset hereditary stroke; CADASIL; Cerebral autosomal dominant arteriopathy with subcortical infarcts and Leukoencephalopathy; Hong Kong Chinese; NOTCH3 mutations
• ISSN: 0967-5868; 1532-2653
• DOI: 10.1016/j.jocn.2018.06.050

•A novel NOTCH3 likely pathogenic variant (p.N1969∗) in the intracellular ankyrin repeat domain is detected.•This novel variant does not affect the number of cysteine residues on the Notch3 receptor and escapes the nonsense mediated mRNA decay.•Findings suggest CADASIL pathogenicity acts from a more downstream part of the Notch signaling pathway.•Under-referral of cases for CADASIL genetic testing is likely. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary stroke syndrome characterized by recurrent stroke and progressive cognitive impairment caused by NOTCH3 mutations. We report here the clinical and molecular findings of three unrelated Hong Kong Chinese families with CADASIL syndrome. Sanger sequencing of genomic DNA revealed a novel heterozygous variant NM_000435.2(NOTCH3):c.[5903_5904insATAA];[5903_5904=] NP_000426.2:p.(Asp1969∗);(Asp1969=) and two previously reported heterozygous mutations NM_000435.2(NOTCH3):c.[328C>T];[328C=] NP_000426.2:p.[(Arg110Cys)];[(Arg110=)] and NM_000435.2(NOTCH3):c.[580T>A];[580T=] NP_000426.2:p.(Cys194Ser);(Cys194=) in the three families respectively. Molecular basis of CADASIL in these three patients were further established. Genetic analysis provides a reliable method for confirming the diagnosis of CADASIL and enables proper genetic counseling and cascade testing.