Next Generation Sequencing for Systematic Assessment of Genetics of Small-Vessel Disease and Lacunar Stroke

Bersano, Anna; Zuffardi, Orsetta; Pantoni, Leonardo; Quaglini, Silvana; Ciccone, Roberto; Vetro, Annalisa; Persico, Alessandra; Denaro, Maria Federica; Micieli, Giuseppe

doi:10.1016/j.jstrokecerebrovasdis.2014.10.019

Cited by 9 publications

(4 citation statements)

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“…Sufficient power can only be achieved by jointly analyzing all data and will likely even necessitate cross-consortia efforts. Furthermore, many consortia have progressed to novel technologies, such as next generation sequencing, which permit further identification of multiple causal variants, including rare variants [53]. …”

Section: Reviewmentioning

confidence: 99%

Genetics of vascular dementia – review from the ICVD working group

Ikram

Bersano²,

Manso-Calderón

et al. 2017

BMC Med

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Background: Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice. Discussion: In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians. Conclusion: The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.

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Section: Reviewmentioning

confidence: 99%

Genetics of vascular dementia – review from the ICVD working group

Ikram

Bersano²,

Manso-Calderón

et al. 2017

BMC Med

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“…An NGS gene panel was also applied to stroke patients. An ongoing, large-sample prospective study, the Small Vessel and Lacunar (SVE-LA) project, designed a screening panel covering 43 genes with monogenic genes, such as NOTCH3 , and polygenic genes, such as interleukin 6 ( IL-6 ) ( 40 ). However, the genes and patients’ clinical phenotype were restricted to SVD, and the number of genes was also limited.…”

Section: Discussionmentioning

confidence: 99%

Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Yuan¹,

Shang²,

Tian³

et al. 2022

Ann Transl Med

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Background The prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients. Methods This multicenter study enrolled cryptogenic stroke patients under 55 years old, and individuals with nonstroke diseases were included as controls. Targeted next-generation sequencing (NGS) was applied with a custom-designed gene panel that included 551 genes. Rare variants were classified into 2 groups: pathogenic variants and variants of unknown significance. Results A total of 153 individuals, including 30 (21 males, 70%; mean age 36.1±10.2 years) in the disease group and 123 (59 males, 48.0%; mean age 40.4±13.1 years) in the control group, were recruited. In the disease group, 32 rare variants were identified. Among these individuals, 18 pathogenic variants in 16 patients were detected, with a 53.3% (16/30) diagnostic yield of monogenic causes for cryptogenic stroke. None of these mutations were observed in the control group. Among the mutant genes, the most prevalent were Notch receptor 3 ( NOTCH3 ), protein kinase AMP-activated noncatalytic subunit gamma 2 ( PRKAG2 ), and ryanodine receptor 2 ( RYR2 ). Genes associated with cardiogenic diseases showed the highest mutation frequency (10/18, 55.6%) followed by genes associated with small-vessel diseases (SVDs) and coagulation disorders. None of the patients with mutations had evident abnormalities in the heart or other systems checked by routine tests. For the imaging phenotype–genotype association analysis, infarctions in both the anterior and posterior cerebral circulation were only observed in patients with genes related to cardiogenic disease. Conclusions In this study, pathogenic variants were identified in nearly half of the young-onset cryptogenic stroke patients, with genes related to cardiogenic diseases being the most frequently mutated. This may have implications for future clinical decision-making, including the development of finer and more sensitive examinations.

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“…In another whole-exome sequencing study, a gene implicated in Charcot-Marie-Tooth disease, SH3TC1 , was associated with WMHs . Understanding of the genetic origins of LS will be advanced by the Small Vessel and Lacunar Project, an ongoing large, prospective study using next-generation sequencing …”

Section: Advances In Understanding Geneticsmentioning

confidence: 99%

Advances in Understanding the Pathophysiology of Lacunar Stroke

et al. 2018

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troke is the second leading cause of death in the world and the leading cause of disability in the United States. 1 Among ischemic strokes, there are different subtypes, including large artery atherosclerosis, cardioembolism, and cerebral small vessel disease (CSVD). Although CSVD has several clinical and radiographic manifestations, lacunar stroke (LS) is prototypical and accounts for 20% to 30% of ischemic strokes. 2,3 Clinically, LS can manifest with several syndromes depending on lesion location. 4 Silent LSs are found in 20% to 50% of healthy elderly people. 5 Lacunar strokes are particularly burdensome, with a 20% recurrence rate, 25% fiveyear mortality, and associated morbidities, such as vascular cognitive impairment. 3 Lacunar strokes, appropriately named given their propensity to form cavities (lacunes), were first described in 1838 (Figure 1). 3 More recently, the Standards for Reporting Vascular Changes on Neuroimaging definitions were developed to standardize terms that describe the appearance of sequelae of CSVD, including recent small subcortical infarcts, lacunes, white matter hyperintensities (WMHs), perivascular spaces, microbleeds, and brain atrophy, on imaging. 6 Lacunar strokes primarily encompass 2 terms: recent small subcortical infarcts, defined as recent infarctions in the territory of 1 perforating arteriole with imaging features or clinical symptoms consistent with occurrence in the previous few weeks, and lacunes, defined as round or ovoid, subcortical, fluid-filled cavities 3 to 15 mm in diameter, consistent with previous acute small subcortical infarcts or hemorrhages in the territory of 1 perforating arteriole. 6 Although this review focuses on LS, other abnormalities that result from CSVD are relevant because there are interrelated mechanisms and treatment implications. For example, recent small subcortical infarcts can also contribute to WMH, 3 and many intracerebral hemorrhages (ICHs) likely result from similar vessel abnormalities. 7 This suggests that patients with LS may have an increased risk for bleeding when taking antithrombotic medications. IMPORTANCE Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.OBSERVATIONS When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis. Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebr...

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Next Generation Sequencing for Systematic Assessment of Genetics of Small-Vessel Disease and Lacunar Stroke

Cited by 9 publications

References 32 publications

Genetics of vascular dementia – review from the ICVD working group

Genetics of vascular dementia – review from the ICVD working group

Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Advances in Understanding the Pathophysiology of Lacunar Stroke

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