New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Abramycheva, N.Y.; Stepanova, M. S.; Калашникова, Л А; Zakharova, M. N.; Maximova, M. Yu.; Tanashyan, M. M.; Лагода, О.В.; Fedotova, E. Yu.; Klyushnikov, S. A.; Konovalov, R. N.; Sakharova, A. Ya.; Иллариошкин, С. Н.

doi:10.1016/j.jns.2015.01.018

Cited by 22 publications

(18 citation statements)

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“…The search for all mutations in Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project showed that only p.H1235L [ 28 ], p.H170R [ 30 , 31 ], p.S497L [ 34 ], p.A1020P [ 36 ], and p.H1133Q [ 34 ] were polymorphisms or subpolymorphic variants, as their MAF was >0.1%.…”

Section: Resultsmentioning

confidence: 99%

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL

Muiño

Gallego-Fábrega

Cullell

et al. 2017

IJMS

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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.

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Section: Resultsmentioning

confidence: 99%

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL

Muiño

Gallego-Fábrega

Cullell

et al. 2017

IJMS

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“…Of these, three amino acid changing variants (p.S497L, p.A1020P and p.H1133Q) were recently reported by Abramycheva et al [15] as normal polymorphisms in Russian CADASIL patients. However, in this study, patient C-3 was found to carry non-cysteine NOTCH3 gene variants (p.S496L and p.A1020P).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, previous work by Markus et al tested the sensitivity of single strand conformation polymorphism (SSCP) analysis for detecting NOTCH3 mutations, with an effective success rate of 80 to 85 % [14]. More recently, He et al reported that varying and population-dependant results in the effectiveness of using the pre-genetic “CADASIL scale” screening tool which evaluates clinical presentations and neuroimaging data in an effort to minimise NOTCH3 gene testing [15, 16]. As such, current diagnosis relies on the screening of all exons by sequencing to identify mutations in NOTCH3 .…”

Section: Discussionmentioning

confidence: 99%

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients

et al. 2016

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BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations. The aim of this study was to develop a new, comprehensive and efficient single assay strategy for complete molecular diagnosis of NOTCH3 mutations through the use of a custom next-generation sequencing (NGS) panel for improved routine clinical molecular diagnostic testing.ResultsOur custom NGS panel identified nine genetic variants in NOTCH3 (p.D139V, p.C183R, p.R332C, p.Y465C, p.C597W, p.R607H, p.E813E, p.C977G and p.Y1106C). Six mutations were stereotypical CADASIL mutations leading to an odd number of cysteine residues in one of the 34 NOTCH3 gene epidermal growth factor (EGF)-like repeats, including three new typical cysteine mutations identified in exon 11 (p.C597W; c.1791C>G); exon 18 (p.C977G; c.2929T>G) and exon 20 (p.Y1106C; c.3317A>G). Interestingly, a novel missense mutation in the CACNA1A gene was also identified in one CADASIL patient. All variants identified (novel and known) were further investigated using in silico bioinformatic analyses and confirmed through Sanger sequencing.ConclusionsNGS provides an improved and effective methodology for the diagnosis of CADASIL. The NGS approach reduced time and cost for comprehensive genetic diagnosis, placing genetic diagnostic testing within reach of more patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0093-z) contains supplementary material, which is available to authorized users.

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“…. There have since been several reports of this mutation in CADASIL patients from central Italy 86 , in one Russian CADASIL patient (a compound heterozygote with NOTCH3:p.Phe984Cys)87 and in a Turkish AD case88 . This variant is not reported in unrelated Chinese cases diagnosed with CADASIL 89 .…”

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confidence: 94%

How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

Dehghani

Brás

Guerreiro

2020

Preprint

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The majority of genome-wide association studies have been conducted using samples with a European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this study, we aimed to illustrate the benefits, to genetic characterization of Alzheimer's disease (AD), in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we have conducted a literature search to understand the contributions of studies, on different populations, to AD genetics. We systematically quantified the number of studies identifying mutations in known disease-causing genes, in a world-wide manner, and discussed the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant SNPs across populations by focusing on loci that show different association profiles between populations (a key example being APOE). This work functions to both highlight how understudied populations have furthered our understanding of AD genetics, and to help us gage our progress in understanding the genetic architecture of this disease in all populations.

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New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Cited by 22 publications

References 41 publications

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients

How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

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