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

Paul J Dunn1,2, Rodney A Lea1, Neven Maksemous1

  • 1Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia.

Human Genetics
|July 8, 2023
PubMed

Insights

Researchers identified novel genes involved in CADASIL-like cerebral small-vessel disease (CSVD) by sequencing patient exomes. Cell-cell adhesion genes and 15 specific genes were implicated in the pathology, expanding our understanding beyond NOTCH3 mutations.

Area of Science:

  • Genomics and Molecular Biology
  • Neurology and Neurogenetics
  • Vascular Biology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic condition linked to NOTCH3 mutations, causing strokes and dementia.
  • A significant portion of clinically suspected CADASIL cases do not have identified NOTCH3 mutations, suggesting other genetic factors are involved.
  • Understanding the molecular mechanisms of CADASIL-related cerebral small-vessel disease (CSVD) is crucial for identifying new therapeutic targets.

Purpose of the Study:

  • To identify novel genetic variants and biological pathways associated with CADASIL-like cerebral small-vessel disease (CSVD) beyond NOTCH3 mutations.
  • To investigate the functional significance of identified genetic variants using gene ontology and mutation burden analysis.
  • To implicate specific genes in the pathology of CADASIL-related CSVD.

Main Methods:

  • Whole exome sequencing was performed on 50 individuals with suspected CADASIL-like CSVD.
  • Gene ontology overrepresentation tests were used to identify affected biological processes.
  • TRAPD software was employed for mutation burden testing of candidate genes against a control dataset (gnomAD v2.1.1).

Main Results:

  • Cell-cell adhesion genes were found to be significantly overrepresented in the study cohort.
  • Fifteen genes, including ARVCF, GPR17, PTPRS, and CELSR1, showed a higher burden of rare, functionally relevant mutations compared to controls.
  • These 15 genes are implicated as novel candidates in CADASIL-related pathology.

Conclusions:

  • This study highlights cell-cell adhesion as a potentially important biological process in CADASIL-related CSVD.
  • Novel candidate genes (ARVCF, GPR17, PTPRS, CELSR1, and 11 others) are implicated in the disease pathology.
  • The findings expand the genetic landscape of CADASIL-like CSVD and offer new avenues for research and potential therapeutic strategies.

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