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

Hung, Ling Yin; Ling, Tsz Ki; Lau, Nike Kwai Cheung; Cheung, Wing Lan; Chong, Yeow Kuan; Sheng, Bun; Kwok, King Ming; Mak, Chloe Miu

doi:10.1016/j.jocn.2018.06.050

Cited by 11 publications

(8 citation statements)

References 22 publications

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“…A heterozygous missense variant (c.5554 G > A) in exon 30 was identified in a Swiss family affected by recurrent stroke-like episodes, migraine, subcortical dementia, and positive GOM deposition. Up to date, there are six cases reported variants outside EGFr to be possible causal of CADASIL (summarized in Supplementary Table 2; Jung et al, 1995;Joutel et al, 1996;Fouillade et al, 2008;Bersano et al, 2012;Hung et al, 2018;Park et al, 2020). We identified three variants outside the EGFr coding region.…”

Section: Discussionmentioning

confidence: 78%

“…Therefore, most previous studies in CADASIL patients only analyzed the NOTCH3 gene by sequencing exons 2-24. However, several studies reported mutations outside the EGFr coding region (exons 25-33) to be possible causal of CADASIL (Jung et al, 1995;Joutel et al, 1996;Fouillade et al, 2008;Bersano et al, 2012;Hung et al, 2018). On the other hand, NOTCH3 mutations are not detected in all biopsy-determined CADASIL patients by sequencing the EGFr encoding region (Peters et al, 2005), suggesting that variants outside the EFGr encoding region require further investigation.…”

Section: Introductionmentioning

confidence: 99%

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NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Sun

Zhou

et al. 2021

Front. Genet.

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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.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Sun

Zhou

et al. 2021

Front. Genet.

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“…Gene examination is the gold standard for the diagnosis of this disease. 6 , 24 In this report, we detected a heterozygous deletion‐insertion mutation, c.512_605delinsA, in exon 4 of NOTCH3 , resulting in amino acid changes in P. G171_A202delinsE. Although there was no association between this heterozygous mutation and CADASIL in HGMD, according to ACMG guidelines, 25 the variation can be rated as a pathogenic variation.…”

Section: Discussionmentioning

confidence: 79%

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation

Liu

Zhang

Wang

et al. 2021

Clinical Laboratory Analysis

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Autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic inherited cerebrovascular disease. The disease is caused by the mutations in NOTCH3 on chromosome 19. 1,2 CADASIL usually starts in the middle age, which is different from the traditional cerebrovascular disease, and it usually has no clear high-risk factors for cerebrovascular disease, with recurrent stroke as the main manifestation, which can be accompanied by cognitive impairment, dementia, mental and emotional disorders, and migraine with aura. 3 The presence of granular osmiophilic material (GOM) in close proximity to smooth muscle cells, pericytes, and endothelial cells is critical for the diagnosis of CADASIL. 4,5 Analysis of all the exons of the NOTCH3 gene is crucial to determine the mutation that causes the pathology. 6,7 The NOTCH3 gene, located on chromosome 19p13, encodes a single-pass transmembrane receptor, which is composed of a large extracellular domain (ECD) with 34 tandem epidermal growth factor-like (EGF) repeats encoded by exons 2-24, where NOTCH3 mutations are commonly found, a transmembrane domain, and an intracellular domain (ICD). [8][9][10] In all, 33 exons and 2321 amino acids constitute NOTCH3. 11 CADASIL is caused by the presence of only one mutation in one of the two alleles of NOTCH3 because pathogenic mutations are dominant in this disease. 12

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“…The incidence and prevalence of CADASIL are difficult to investigate and the reported data are limited since CADASIL is clinically and genetically heterogeneous ( Kilarski et al, 2015 ; Rutten et al, 2016 ; Tang et al, 2019 ). To date, more than 300 mutations of NOTCH3 have been recorded in CADASIL patients ( Hung et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

Wang

et al. 2021

Front. Mol. Biosci.

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Background: Autosomal dominant spinocerebellar ataxia type 37 (SCA37) and Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) result from DAB1 and NOTCH3 gene mutations, respectively.Methods: In addition to conventional diagnostic methods, next-generation sequencing (NGS) and Sanger sequencing were performed to define and confirm the DAB1 and NOTCH3 gene mutation for a Chinese pedigree. Bioinformatics analysis was also applied for the mutated DAB1 and NOTCH3 protein using available software tools.Results: Brain magnetic resonance imaging shows diffuse leukoencephalopathy and cerebellar atrophy in the proband. NGS and Sanger sequencing identified two novel heterozygous mutations: NM_021080:c.318T > G (p.H106Q) in the DAB1 gene and NM_000435:c.3298C > T (p.R1100C) in the NOTCH3 gene. Bioinformatics analysis suggested that the DAB1 and NOTCH3 gene mutations are disease-causing and may be responsible for the phenotypes.Conclusion: This is the first report of a pedigree with both SAC37 and CADASIL phenotypes carrying corresponding gene mutations. Mutations in the NOTCH3 gene may promote the clinical presentation of spinocerebellar ataxia type 37 caused by mutations in the DAB1 gene. In addition to general examinations, it is vital for physicians to apply molecular genetics to get an accurate diagnosis in the clinic, especially for rare diseases.

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

Cited by 11 publications

References 22 publications

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation

Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

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