Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report

He, Rong; Li, Huan; Sun, Yu; Chen, Menglong; Wang, Liang; Zhu, Yunping; Zhou, Cheng

doi:10.1186/s12883-020-01660-0

Cited by 7 publications

(2 citation statements)

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“…Both SNPs have been previously reported in CADASIL patients. 24,25 We assessed the functionality of the detected rare SNPs using Sorting Intolerant from Tolerant, PolyPhen2, Mutation Taster, and Combined Annotation Dependent Depletion. Among 62 rare SNPs, 49 (79.0%) were classified as pathogenic or possibly pathogenic by at least 2 of the 4 prediction tools.…”

Section: Resultsmentioning

confidence: 99%

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

Liu

Yao

Dai

et al. 2021

Stroke

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Background and Purpose: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. Methods: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. Results: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P =0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. Conclusions: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

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Section: Resultsmentioning

confidence: 99%

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

Liu

Yao

Dai

et al. 2021

Stroke

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“…CADASIL is inherited in an autosomal dominant manner. A few cases of homozygous variants in the NOTCH3 gene have been published, not always with a more severe phenotype than heterozygotes (He et al, 2020). Cases of CADASIL associated with de novo pathogenic variants are very rare.…”

Section: Introductionmentioning

confidence: 99%

First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection

Moreno-Garcı́a

Arteche‐López

Álvarez-Mora

et al. 2020

American J of Med Genetics Pt A

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next‐generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling.

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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Chabriat

2024

Stroke Genetics

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Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report

Cited by 7 publications

References 20 publications

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

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