A stroke gene panel for whole-exome sequencing

Ilinca, Andreea; Samuelsson, Sofie; Piccinelli, Paul; Soller, Maria; Kristoffersson, Ulf; Lindgren, Arne

doi:10.1038/s41431-018-0274-4

Cited by 27 publications

(41 citation statements)

References 21 publications

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“…Details of library preparation and data processing are shown in Supplemental Materials. The stroke-gene panels SGP1 and SGP2 compiled by Ilinca et al (2019) 11 was utilized in the variant analysis. Variants located in 168 genes/loci known to be associated with monogenic causes of stroke 11 were extracted from the whole exome data.…”

Section: Whole-exome Sequencing (Wes)mentioning

confidence: 99%

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Whole-exome sequencing of Finnish patients with vascular cognitive impairment

et al. 2020

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Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2 and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.

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Section: Whole-exome Sequencing (Wes)mentioning

confidence: 99%

“…The stroke-gene panels SGP1 and SGP2 compiled by Ilinca et al (2019) 11 was utilized in the variant analysis. Variants located in 168 genes/loci known to be associated with monogenic causes of stroke 11 were extracted from the whole exome data. Mitochondrial genes were excluded from this analysis.…”

Section: Whole-exome Sequencing (Wes)mentioning

confidence: 99%

Whole-exome sequencing of Finnish patients with vascular cognitive impairment

et al. 2020

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“…We examined whole-genome sequencing (WGS) data from nuclear and mitochondrial DNA from the proband for the presence of rare genetic variation in 31 known genes for monogenic cSVD-related stroke from our Stroke Gene Panel 6 and recent publications, 2 genes for cerebral amyloid angiopathy with no known association to stroke, and genes that are known causes of familial basal ganglia calcification. We considered all variants up to an allele frequency of 5% in 1000 Genomes, 9 SweGene, 10 and ExAC 11 (supplemental data e1).…”

Section: Methodsmentioning

confidence: 99%

“… 5 The presence and sometimes disease-specific appearance of neuroimaging biomarkers facilitate phenotyping studies of cSVD-associated stroke compared with other subtypes of stroke, and several genetically defined conditions resulting in cSVD stroke have been identified to date. Supplemental data e1 and table 1( links.lww.com/NXG/A364 ) lists the known monogenic forms of stroke due to cSVD, including the 22 genes we previously compiled 6 and additional entities described since that publication. Nevertheless, the pathogenic mechanisms of these diseases remain poorly understood, 7 and as a consequence, the possibilities to treat stroke related to cSVDs remained modest.…”

mentioning

confidence: 99%

“…Supplemental data e1 and table 1(links. lww.com/NXG/A364) lists the known monogenic forms of stroke due to cSVD, including the 22 genes we previously compiled 6 and additional entities described since that publication. Nevertheless, the pathogenic mechanisms of these diseases remain poorly understood, 7 and as a consequence, the possibilities to treat stroke related to cSVDs remained modest.…”

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MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor

et al. 2021

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ObjectiveTo describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.MethodsWe studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.ResultsFifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.ConclusionsOur data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.

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Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants

Härtl

Hartberger²,

Wunderlich³

et al. 2022

J Neurol

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Background Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. Material and methods We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. Results Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry’s disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). Conclusion Genetic screening for Fabry’s disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

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A stroke gene panel for whole-exome sequencing

Cited by 27 publications

References 21 publications

Whole-exome sequencing of Finnish patients with vascular cognitive impairment

Whole-exome sequencing of Finnish patients with vascular cognitive impairment

MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor

Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants

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