RESUMEN
BACKGROUND: Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear. METHODS: Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. RESULTS: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001). CONCLUSIONS: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.
Asunto(s)
CADASIL/genética , Demencia Vascular/genética , Predisposición Genética a la Enfermedad , Receptor Notch3/genética , Accidente Cerebrovascular/genética , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Demencia Vascular/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
BACKGROUND: Cerebral small-vessel disease (cSVD) is the leading monogenic cause of stroke. Despite genetic screening in routine diagnosis, many cases remain without a known causative variant. Using a cohort with suspected familial cSVD and whole-genome sequencing, we screened for variants in genes associated with monogenic cSVD and searched for novel variants associated with the disease. METHODS AND RESULTS: Rare variants were identified in whole-genome sequencing data from the NBR (National Institute for Health Research BioResource Rare Disease) study. Pathogenic variants in known monogenic cSVD genes were identified. Gene-based burden tests and family analysis were performed to identify novel variants associated with familial cSVD. A total of 257 suspected cSVD cases (mean ± SD age, 56.2 ± 16.1 years), and 13 086 controls with other nonstroke diseases (5874 [44.9%] men) were studied. A total of 8.9% of the cases carried a variant in known cSVD genes. Excluding these known causes, 23.6% of unrelated subjects with cSVD carried predicted deleterious variants in the Genomics England gene panel, but no association was found with cSVD in burden tests. We identified potential associations with cSVD in noncoding genes, including RP4-568F9.3 (adjusted P = 7.1 × 10-25), RP3-466I7.1 (adjusted P = 8.9 × 10-16), and ZNF209P (adjusted P = 1.0 × 10-15), and matrisomal genes (adjusted P = 5.1 × 10-6), including FAM20C, INHA, LAMC1, and VWA5B2. CONCLUSIONS: Predicted deleterious variants in known cSVD genes were present in 23.6% of unrelated cases with cSVD, but none of the genes were associated with the disease. Rare variants in noncoding and matrisomal genes could potentially contribute to cSVD development. These genes could play a role in tissue development and brain endothelial cell function. However, further studies are needed to confirm their pathophysiological roles.
Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Predisposición Genética a la Enfermedad , Secuenciación Completa del Genoma , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Variación Genética , Linaje , Estudios de Casos y Controles , Fenotipo , Mutación , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations. METHODS: We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk. RESULTS: We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains. DISCUSSION: NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.
RESUMEN
Importance: It is uncertain whether typical variants causing monogenic stroke are associated with cerebrovascular disease in the general population and why the phenotype of these variants varies so widely. Objective: To determine the frequency of pathogenic variants in the 3 most common monogenic cerebral small vessel diseases (cSVD) and their associations with prevalent and incident stroke and dementia. Design, Setting, and Participants: This cohort study is a multicenter population-based study of data from UK Biobank participants recruited in 2006 through 2010, with the latest follow-up in September 2021. A total of 9.2 million individuals aged 40 to 69 years who lived in the United Kingdom were invited to join UK Biobank, of whom 5.5% participated in the baseline assessment. Participants eligible for our study (n = 454â¯756, excluding 48â¯569 with incomplete data) had whole-exome sequencing and available data pertaining to lacunar stroke-related diseases, namely stroke, dementia, migraine, and epilepsy. Exposures: NOTCH3, HTRA1, and COL4A1/2 pathogenic variants in monogenic stroke; Framingham cardiovascular risk; and ischemic stroke polygenic risk. Main Outcomes and Measures: Primary outcomes were prevalent and incident stroke and dementia. Odds ratios (ORs) and hazard ratios (HRs) were adjusted for age, sex, ethnicity, exome sequencing batch, and top 10 genetic principal components. Results: Of the 454â¯756 participants (208â¯027 [45.8%] men; mean [SD] age, 56.5 [8.1] years), 973 participants carried NOTCH3 variants, 546 carried HTRA1 variants, and 336 carried COL4A1/2 variants. Variant carriers were at least 66% more likely to have had stroke. NOTCH3 carriers had increased vascular dementia risk (OR, 5.42; 95% CI, 3.11-8.74), HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41), and COL4A1/2 carriers an increased intracerebral hemorrhage risk (OR, 3.56; 95% CI, 1.34-7.53). NOTCH3 variants were associated with incident ischemic stroke and vascular dementia. NOTCH3 and HTRA1 variants were associated with magnetic resonance imaging markers of cSVD. Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers. Variant location was also associated with risk. Conclusions and Relevance: In this cohort study, pathogenic variants associated with rare monogenic stroke were more common than expected in the general population and associated with stroke and dementia. Cardiovascular risk burden is associated with the penetrance of such variants. Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants. This lays the foundation for future studies to evaluate the effect of early identification before symptom onset on mitigating stroke and dementia risk.