NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

BackgroundCysteine-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.MethodsCysteine-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.ResultsOf 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).ConclusionsCysteine-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.

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NOTCH3 variants are common in the general population and associated with stroke and vascular dementia: an analysis of 200,000 participants

10.1101/2020.12.14.20248151 ◽

2020 ◽

Author(s):

Bernard PH Cho ◽

Stefania Nannoni ◽

Eric L Harshfield ◽

Daniel J Tozer ◽

Stefan Gräf ◽

...

Keyword(s):

White Matter ◽

General Population ◽

Vascular Dementia ◽

Exome Sequencing ◽

Visual Analysis ◽

White Matter Hyperintensity ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Increased Risk ◽

Mri Changes

ABSTRACTBackgroundCysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL, 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 remains unclear.MethodsCysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200,632). Frequency of stroke, 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.ResultsOf 200,632 participants with exome sequencing data available, 443 (∼1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjusting for age, sex, and ancestry principal components, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0003), and vascular dementia (OR: 5.03, p=0.007), and increased WMH volume (standardised difference: 0.52, p<0.001), and white matter ultrastructural damage on DTI-PSMD (standardised difference: 0.71, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 4.83, p<0.001) and cerebral microbleeds (OR: 3.61, p<0.001). WMH prevalence was most increased in the anterior temporal lobes (OR: 6.92, p<0.001) and external capsule (OR: 12.44, p<0.001).ConclusionsCysteine-changing NOTCH3 variants are common in the general population and are risk factors for apparently “sporadic” stroke and vascular dementia. They are associated with MRI changes of SVD, in a distribution similar to that seen in CADASIL.

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Prior intracerebral hemorrhage and white matter hyperintensity burden on recurrent stroke risk

Scientific Reports ◽

10.1038/s41598-021-96809-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jong-Ho Park ◽

Sun U. Kwon ◽

Hyuk Sung Kwon ◽

Sung Hyuk Heo

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Intracerebral Hemorrhage ◽

Hemorrhagic Stroke ◽

Small Vessel Disease ◽

Recurrent Stroke ◽

White Matter Hyperintensity ◽

Major Adverse Cardiovascular Events ◽

Stroke Incidence ◽

Increased Risk

AbstractPrior intracerebral hemorrhage (ICH) is associated with increased risk of ischemic stroke. Since white matter hyperintensity (WMH) is associated with ischemic stroke and ICH, this study aimed to evaluate the relationship between ICH and the risk of recurrent stroke by WMH severity. From a prospective multicenter database comprising 1454 noncardioembolic stroke patients with cerebral small-vessel disease, patients were categorized by presence or absence of prior ICH and WMH severity: mild-moderate WMH (reference); advanced WMH; ICH with mild-moderate WMH; and ICH with advanced WMH. Among patients with ICH, the association with stroke outcomes by WMH burden was further assessed. The primary endpoint was ischemic stroke and hemorrhagic stroke. The secondary endpoint was major adverse cardiovascular events (MACE): stroke/coronary heart disease/vascular death. During the mean 1.9-year follow-up period, the ischemic stroke incidence rate per 100 person-years was 2.7, 4.0, 2.5, and 8.1 in increasing severity, and the rate of hemorrhagic stroke was 0.7, 1.3, 0.6, and 2.1, respectively. The risk of ischemic stroke was higher in ICH with advanced WMH (adjusted HR 2.62; 95% CI 1.22−5.60) than the reference group, while the risk of hemorrhagic stroke trended higher (3.75, 0.85–16.53). The risk of MACE showed a similar pattern in ICH with advanced WMH. Among ICH patients, compared with mild WMH, the risk of ischemic stroke trended to be higher in advanced WMH (HR 3.37; 95% CI 0.90‒12.61). Advanced WMH was independently associated with an increased risk of hemorrhagic stroke (HR 33.96; 95% CI 1.52−760.95). Given the fewer rate of hemorrhagic stroke, the risk of hemorrhagic stroke might not outweigh the benefits of antiplatelet therapy for secondary prevention.

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The association between lacunes and white matter hyperintensity features on MRI: The SMART-MR study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18800463 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2486-2496 ◽

Cited By ~ 5

Author(s):

Rashid Ghaznawi ◽

Mirjam I Geerlings ◽

Myriam G Jaarsma-Coes ◽

Maarten HT Zwartbol ◽

Hugo J Kuijf ◽

...

Keyword(s):

White Matter ◽

Functional Outcomes ◽

Small Vessel Disease ◽

Brain Magnetic Resonance Imaging ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Intracranial Volume ◽

Increased Risk ◽

Magnetic Resonance Imaging Mri ◽

Mr Study

Lacunes and white matter hyperintensities (WMHs) are features of cerebral small vessel disease (CSVD) that are associated with poor functional outcomes. However, how the two are related remains unclear. In this study, we examined the association between lacunes and several WMH features in patients with a history of vascular disease. A total of 999 patients (mean age 59 ± 10 years) with a 1.5 T brain magnetic resonance imaging (MRI) scan were included from the SMART-MR study. Lacunes were scored visually and WMH features (volume, subtype and shape) were automatically determined. Analyses consisted of linear and Poisson regression adjusted for age, sex, and total intracranial volume (ICV). Patients with lacunes (n = 188; 19%) had greater total (B = 1.03, 95% CI: 0.86 to 1.21), periventricular/confluent (B = 1.08, 95% CI: 0.89 to 1.27), and deep (B = 0.71, 95% CI: 0.44 to 0.97) natural log-transformed WMH volumes than patients without lacunes. Patients with lacunes had an increased risk of confluent type WMHs (RR = 2.41, 95% CI: 1.98 to 2.92) and deep WMHs (RR = 1.41, 95% CI: 1.22 to 1.62) and had a more irregular shape of confluent WMHs than patients without lacunes, independent of total WMH volume. In conclusion, we found that lacunes on MRI were associated with WMH features that correspond to more severe small vessel changes, mortality, and poor functional outcomes.

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ETumorMetastasis: A Network-based Algorithm Predicts Clinical Outcomes Using Whole-exome Sequencing Data of Cancer Patients

Genomics Proteomics & Bioinformatics ◽

10.1016/j.gpb.2020.06.009 ◽

2021 ◽

Cited By ~ 1

Author(s):

Jean-Sébastien Milanese ◽

Chabane Tibiche ◽

Naif Zaman ◽

Jinfeng Zou ◽

Pengyong Han ◽

...

Keyword(s):

Exome Sequencing ◽

Cancer Patients ◽

Clinical Outcomes ◽

Whole Exome Sequencing ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data

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Variable Phenotypes of Epilepsy, Intellectual Disability, and Schizophrenia Caused by 12p13.33–p13.32 Terminal Microdeletion in a Korean Family: A Case Report and Literature Review

Genes ◽

10.3390/genes12071001 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1001

Author(s):

Jiyoon Han ◽

Joonhong Park

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Environmental Influence ◽

Copy Number Variations ◽

Genetic Modifiers ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Korean Family ◽

Coverage Analysis ◽

Patient Will

A simultaneous analysis of nucleotide changes and copy number variations (CNVs) based on exome sequencing data was demonstrated as a potential new first-tier diagnosis strategy for rare neuropsychiatric disorders. In this report, using depth-of-coverage analysis from exome sequencing data, we described variable phenotypes of epilepsy, intellectual disability (ID), and schizophrenia caused by 12p13.33–p13.32 terminal microdeletion in a Korean family. We hypothesized that CACNA1C and KDM5A genes of the six candidate genes located in this region were the best candidates for explaining epilepsy, ID, and schizophrenia and may be responsible for clinical features reported in cases with monosomy of the 12p13.33 subtelomeric region. On the background of microdeletion syndrome, which was described in clinical cases with mild, moderate, and severe neurodevelopmental manifestations as well as impairments, the clinician may determine whether the patient will end up with a more severe or milder end‐phenotype, which in turn determines disease prognosis. In our case, the 12p13.33–p13.32 terminal microdeletion may explain the variable expressivity in the same family. However, further comprehensive studies with larger cohorts focusing on careful phenotyping across the lifespan are required to clearly elucidate the possible contribution of genetic modifiers and the environmental influence on the expressivity of 12p13.33 microdeletion and associated characteristics.

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UTILIZATION OF WHOLE EXOME SEQUENCING DATA TO IDENTIFY CLINICALLY RELEVANT PHARMACOGENOMIC VARIANTS IN INFLAMMATORY BOWEL DISEASE

Gastroenterology ◽

10.1053/j.gastro.2021.01.119 ◽

2021 ◽

Vol 160 (3) ◽

pp. S43

Author(s):

Daniel Mulder ◽

Sam Khalouei ◽

Neil Warner ◽

Claudia Gonzaga-Jauregui ◽

Peter Church ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Inflammatory Bowel

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FC 011KIDNEYNETWORK: USING KIDNEY DERIVED GENE EXPRESSION DATA TO PREDICT AND PRIORITIZE NOVEL GENES INVOLVED IN KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab131.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Floranne Boulogne ◽

Laura Claus ◽

Henry Wiersma ◽

Roy Oelen ◽

Floor Schukking ◽

...

Keyword(s):

Gene Expression ◽

Kidney Disease ◽

Candidate Gene ◽

Exome Sequencing ◽

Rna Sequencing ◽

Expression Patterns ◽

Genetic Diagnosis ◽

Specific Gene ◽

Sequencing Data ◽

Exome Sequencing Data

Abstract Background and Aims Genetic testing in patients with suspected hereditary kidney disease does not always reveal the genetic cause for the patient's disorder. Potentially pathogenic variants can reside in genes that are not known to be involved in kidney disease, which makes it difficult to prioritize and interpret the relevance of these variants. As such, there is a clear need for methods that predict the phenotypic consequences of gene expression in a way that is as unbiased as possible. To help identify candidate genes we have developed KidneyNetwork, in which tissue-specific expression is utilized to predict kidney-specific gene functions. Method We combined gene co-expression in 878 publicly available kidney RNA-sequencing samples with the co-expression of a multi-tissue RNA-sequencing dataset of 31,499 samples to build KidneyNetwork. The expression patterns were used to predict which genes have a kidney-related function, and which (disease) phenotypes might be caused when these genes are mutated. By integrating the information from the HPO database, in which known phenotypic consequences of disease genes are annotated, with the gene co-expression network we obtained prediction scores for each gene per HPO term. As proof of principle, we applied KidneyNetwork to prioritize variants in exome-sequencing data from 13 kidney disease patients without a genetic diagnosis. Results We assessed the prediction performance of KidneyNetwork by comparing it to GeneNetwork, a multi-tissue co-expression network we previously developed. In KidneyNetwork, we observe a significantly improved prediction accuracy of kidney-related HPO-terms, as well as an increase in the total number of significantly predicted kidney-related HPO-terms (figure 1). To examine its clinical utility, we applied KidneyNetwork to 13 patients with a suspected hereditary kidney disease without a genetic diagnosis. Based on the HPO terms “Renal cyst” and “Hepatic cysts”, combined with a list of potentially damaging variants in one of the undiagnosed patients with mild ADPKD/PCLD, we identified ALG6 as a new candidate gene. ALG6 bears a high resemblance to other genes implicated in this phenotype in recent years. Through the 100,000 Genomes Project and collaborators we identified three additional patients with kidney and/or liver cysts carrying a suspected deleterious variant in ALG6. Conclusion We present KidneyNetwork, a kidney specific co-expression network that accurately predicts what genes have kidney-specific functions and may result in kidney disease. Gene-phenotype associations of genes unknown for kidney-related phenotypes can be predicted by KidneyNetwork. We show the added value of KidneyNetwork by applying it to exome sequencing data of kidney disease patients without a molecular diagnosis and consequently we propose ALG6 as a promising candidate gene. KidneyNetwork can be applied to clinically unsolved kidney disease cases, but it can also be used by researchers to gain insight into individual genes to better understand kidney physiology and pathophysiology. Acknowledgments This research was made possible through access to the data and findings generated by the 100,000 Genomes Project; http://www.genomicsengland.co.uk.

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