Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke

Cho, Bernard P. H.; Harshfield, Eric L.; Al-Thani, Maha; Tozer, Daniel J.; Bell, Steven; Markus, Hugh S.

doi:10.1001/jamaneurol.2022.3832

Cited by 34 publications

(28 citation statements)

References 39 publications

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“…Some studies identify differences in penetrance, expressivity, and a globally increased risk of stroke and/or vascular dementia . Cho et al reported consistent findings: pathogenic variants in all 3 genes were markedly more frequent than expected based on prevalence of clinical disease phenotypes thought to be caused by these variants. This was most notable in NOTCH3 where 1 in 467 patients were heterozygous variant carriers vs the estimated prevalence of CADASIL (4:100 000) yielding a more than 50-fold difference.…”

supporting

confidence: 87%

“…In this issue of JAMA Neurology , Cho et al evaluate key questions of penetrance, expressivity, and modulation of monogenic stroke in a methodologically rigorous study of 454 756 UK Biobank participants with whole-exome sequencing data. They focus on pathogenic variants in the 3 most common monogenic cerebral small-vessel diseases (cSVDs): NOTCH3 , HTRA1 , and COL4A1/2 .…”

mentioning

confidence: 99%

“…Only 22 patients in this study were carriers of NOTCH3 EGFr 1-6 (associated with severe CADASIL) and we cannot know if/how much cardiovascular risk reduction would benefit this subpopulation. The foundation developed by Cho et al creates a launchpad for future research to explore these critical questions regarding molecular mechanisms/interactions, intermediate phenotypes, causation, and treatment response.…”

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confidence: 99%

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Monogenic Stroke—Can We Overcome Nature With Nurture?

Jha

2022

JAMA Neurol

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Although genetic underpinnings of several neurological disorders like epilepsy have been described as early as fourth century BCE in the Corpus Hippocraticum, 1 discoveries in stroke have been more recent. One of the first reports demonstrating the importance of heredity in stroke pathogenesis occurred in 1974 with the generation of the stroke-prone spontaneously hypertensive rat. 2 This strain was created using selective breeding and has endured as a valuable asset in contemporary stroke research. Nonetheless, half a century later, the precise genetic determinants even in this single, highly specific rodent stroke phenotype have not been completely elucidated despite immense advances in next-generation sequencing and genome mapping. 3,4 In humans, the role of genetics in stroke is exponentially more complex. Stroke is heterogeneous, as are its predisposing risk factors, which also have their own genetic contributors. Genetics may either mediate or moderate stroke via multiple mechanisms. Genome-wide association studies since 2007 have identified several common loci and variants that typically account for a small proportion of the heritable risk of stroke, stroke subtypes, or conventional stroke risk factors. 5 Monogenic stroke has classically resided on the other end of the continuum, where rare variants in a single gene are often thought to cause diseases. Here, the genetic alteration may contribute to inherited syndromes where stroke is the primary phenotype (eg, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), or multisystem disorders that include stroke as a manifestation (eg, sickle cell anemia). 6 The causative paradigm in monogenic stroke has evolved over the past decade with increasing recognition of variability in penetrance, expressivity, and potential for modulation by risk factors and other genes. [7][8][9][10]

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confidence: 87%

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confidence: 99%

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Monogenic Stroke—Can We Overcome Nature With Nurture?

Jha

2022

JAMA Neurol

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“…37 However, addressing vascular risk factors for sporadic vascular disease may delay onset, modify severity, or prolong the course for individuals with CADASIL and other inherited CSVDs. 25 Thus, securing a diagnosis may prove important for clinical practice and research.…”

Section: Diagnostic Approach To Cadasil and Other Genetic Csvdsmentioning

confidence: 99%

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association

Meschia,

Worrall,

Elahi

et al. 2023

Stroke

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Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

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“…Recent research by Cho et al highlighted an increased risk of stroke and dementia in variant carriers of monogenic stroke genes. 4 Therefore, genetic screening using stroke gene panels could offer fresh insights for risk factor management beyond conventional vascular risk factors.We are truly impressed by the comprehensive work conducted by Härtl et al, which detected monogenic diseases in 2.9% of patients and genetic risk factors in additional 2.9% of patients. 5 This precision in genetic classification and risk assessment is invaluable.…”

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confidence: 99%

Reply to “Clinical Relevance of Genetic Variants in Juvenile Stroke Patients: A Plea for a Precise Classification”

Park

Lee

Cheong³

et al. 2023

Annals of Neurology

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We appreciate the interest and comments made by Härtl et al. in response to our study on pathogenic or likely pathogenic variants in the Korean young stroke population. 1 Their thoughtful feedback underscores the importance of the clinical interpretation of genetic variants, which we too acknowledge. We would like to address each point raised by Härtl et al.Härtl et al. mentioned the variants c.*38G > A and c.1990C > T in ABCC6. We classified them based on the version of the ClinVar database available at the time of our genetic analysis in October 2020. This may vary from the classification in the updated version of ClinVar. The classification may indeed change over time as more data become available, potentially necessitating re-counseling of patients and their families.We agree with Härtl et al. that the presence of pathogenic or likely pathogenic genetic variants does not necessarily imply that patients will exhibit the phenotype of the genetic disorder. Indeed, some individuals may not display the typical phenotype throughout their lives, despite having pathogenic variants. This is particularly observed in individuals with heterozygous variants.The p.Arg4810Lys variant in RNF213, as highly relevant to Moyamoya disease, is particularly significant in Asian individuals with Moyamoya disease. 2 Recent studies have revealed meaningful progression of intracranial artery stenosis in individuals carrying this variant over a median 10-year follow-up period. 3 Furthermore, patients with variants in NOTCH3 may not exhibit the full-blown clinical and imaging characteristics of CADASIL at the time of stroke occurrence. The classification of incomplete penetrance for these variants poses a challenge, and further research is necessary. It would be premature to definitively label this as incomplete penetrance.Pathogenic or likely pathogenic variants in monogenic stroke genes may serve more as risk factors than as definitive determinants of stroke. Recent research by Cho et al. highlighted an increased risk of stroke and dementia in variant carriers of monogenic stroke genes. 4 Therefore, genetic screening using stroke gene panels could offer fresh insights for risk factor management beyond conventional vascular risk factors.We are truly impressed by the comprehensive work conducted by Härtl et al., which detected monogenic diseases in 2.9% of patients and genetic risk factors in additional 2.9% of patients. 5 This precision in genetic classification and risk assessment is invaluable. We sincerely appreciate Härtl et al.'s insights regarding the importance of precise genetic evaluation in numerous neurological diseases, including juvenile stroke.

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Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke

Cited by 34 publications

References 39 publications

Monogenic Stroke—Can We Overcome Nature With Nurture?

Monogenic Stroke—Can We Overcome Nature With Nurture?

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association

Reply to “Clinical Relevance of Genetic Variants in Juvenile Stroke Patients: A Plea for a Precise Classification”

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