How common are single gene mutations as a cause for lacunar stroke?

Tan, Rhea; Traylor, Matthew; Mégy, Karyn; Duarte, Daniel; Shamardina, Olga; Mapeta, Rutendo; Ouwehand, Willem H.; Gräf, Stefan; Downes, Kate; Markus, Hugh S.

doi:10.1212/wnl.0000000000008544

Cited by 38 publications

(46 citation statements)

References 51 publications

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“…Hara et al have indicated that HtrA1 is the causative gene of Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a genetic cause of stroke in the young 21 . Recently, two rare monogenic variants were identified by target gene sequencing for younger onset lacunar stroke 23 . Patients with CARASIL are characterized by ischemic, non-hypertensive with associated alopecia and spondylosis 24 - 26 .…”

Section: Introductionmentioning

confidence: 99%

HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke

Tian¹,

Tang²,

Yang³

et al. 2021

Int. J. Med. Sci.

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High temperature requirement protein A1 (HtrA1) was identified as the causative gene of autosomal recessive arteriopathy and associated with lacunar ischemic stroke (IS) in European. This study aimed at evaluating the association of HTRA1 with IS and four tagging single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of 4,098 Chinese. The mRNA level of HTRA1 in 72 IS cases and 72 hypertension controls were measured and compared. In whole population, SNP rs2268350 (C>T) was significantly associated with IS incidence (P=0.034). Stratification analysis observed significant association of rs2268350 in male, smoking and drinking populations, rs2672587 (C>G) in smoking and nonsmoking populations and rs3793917 (C>G) in smoking, nonsmoking and nondrinking populations with stroke respectively (P<0.05). The additive interaction and multiplicative interaction between rs2268350 and smoking were both of significant (P<0.05) after adjustment for the covariates. There was a cumulated risk of IS among genotypes of rs3793917 (P=0.009) and rs2672587 (P=0.047) in smoking population. The mRNA level of HTRA1 in non-smokers with rs2268350 CC was significantly higher than smokers with rs2268350 CT/TT (P=0.046) in IS cases. Our findings support that HTRA1 confers the genetic susceptibility to IS and smoking might modify the genetic effect of HTRA1 on IS by suppressing HTRA1 mRNA expression.

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Section: Introductionmentioning

confidence: 99%

HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke

Tian¹,

Tang²,

Yang³

et al. 2021

Int. J. Med. Sci.

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“…Lee et al reported that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of 7,038 healthy controls (0.9%), 17 of 800 patients with ischemic stroke (2.1%), and 16 of 245 patients with small vessel occlusion stroke (6.5%) from the Taiwan Biobank and that the other two cysteine-altering mutations (p.C853Y, and p.C884Y) were rarely detected (Lee et al, 2020). Furthermore, from the UK DNA Lacunar Stoke Study, Tan et al identified single gene mutations in 14 patients (eight cysteine-altering NOTCH3 variants in 11 patients, two HTRA1 variants in two patients, and one missense COL4A1 variant in one patient) among 950 patients with younger-onset apparently sporadic small vessel disease stroke using a targeted sequencing panel (14 of 950; 1.5%; Tan et al, 2019). These results strongly support our findings, which indicate that NOTCH3 gene mutations may be involved in some cases of lacunar infarction, which is a representative small vessel disease.…”

Section: Discussionmentioning

confidence: 99%

“…First, this study is based on a relatively small number of patient because the genetic examination of all 1,094 patients was impractical in terms of cost and time. Patients aged 60-70 years and/or with white matter disease could be good targets for genetic testing (Tan et al, 2019;Lee et al, 2020). Age (60 years or younger), hypertension, and white matter lesions were used as criteria for patient selection in this study but these cohort selection criteria could be seen as arbitrary.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Okada

Washida

Irie

et al. 2020

Front. Aging Neurosci.

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Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions.Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2-24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA.Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58. 2 [11.6-292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively. Conclusion:Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be Okada et al.NOTCH3 Mutations Among Lacunar Infarctions underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.

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“…In two patients with VCI-SVD, we identified one patient with a heterozygous pathogenic missense p.P285L variant (NM_002775: c.854C>A) as well as one patient with a heterozygous pathogenic nonsense p.R302 * variant (NM_002775.5: c.904C>T) in the HtrA serine peptidase 1 gene (HTRA1). Both variants is located in the serine protease domain and had been previously reported to be associated with HTRA1-cerebral small vessel disease /CADASIL2 (18)(19)(20)(21).…”

Section: Genetic Variantsmentioning

confidence: 99%

High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy

et al. 2021

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Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. We performed sequencing using a custom-designed panel of 200 neurodegeneration-associated genes on 45 patients with young-onset cognitive impairment with leukodystrophy, and classified them based on van der Knaap et al.'s MRI diagnostic algorithm. We found that 20/45 (44.4%) patients carried pathogenic variants or novel variants predicted to be pathogenic (one in CSF1R, two in HTRA1 and 17 in NOTCH3). All patients with an established genetic diagnosis had an MRI brain pattern consistent with a specific genetic condition/s. More than half (19/37, 51.4%) of patients with MRI changes consistent with vascular cognitive impairment secondary to small vessel disease (VCI-SVD) had pathogenic variants, including all patients with pathogenic NOTCH3 (17/19, 89.5%) and HTRA1 variants (2/19, 11.5%). Amongst patients harboring pathogenic NOTCH3 variants, 13/17 (76.5%) carried the p.R544C variant seen predominantly in East Asians. Anterior temporal white matter involvement was seen only in patients with pathogenic NOTCH3 variants (6/17, 35.3%). Overall, we demonstrated a high diagnostic utility incorporating a targeted neurodegeneration gene panel and MRI-based diagnostic algorithms in young-onset cognitive impairment patients with leukodystrophy.

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How common are single gene mutations as a cause for lacunar stroke?

Cited by 38 publications

References 51 publications

HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke

HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy

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