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. 2023 Sep;142(9):1361-1373.
doi: 10.1007/s00439-023-02584-8. Epub 2023 Jul 8.

Exonic mutations in cell-cell adhesion may contribute to CADASIL-related CSVD pathology

Paul J Dunn  1   2 , Rodney A Lea  1 , Neven Maksemous  1 , Robert A Smith  1 , Heidi G Sutherland  1 , Larisa M Haupt  1   3   4 , Lyn R Griffiths  5
Affiliations

Exonic mutations in cell-cell adhesion may contribute to CADASIL-related CSVD pathology

Paul J Dunn et al. Hum Genet. 2023 Sep.

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15-23% of individuals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 individuals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell-cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF < 0.001) and predicted functionally relevant (SIFT < 0.05, PolyPhen > 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF, GPR17, PTPRS, and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Results from the over-representation tests, investigating the top 15 hits for A PANTHER GO-slim biological processes, B PANTHER GO-slim molecular function, and C PANTHER GO-slim protein classes based on the PANTHER GO-slim overrepresentation test
Fig. 2
Fig. 2
A gene expression map of brain tissues for the genes identified with candidate disease-causing mutations in the CADASIL-related CSVD cohort
See this image and copyright information in PMC

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