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Updated: Jun 4, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort
Paul J Dunn1, Neven Maksemous2, Robert A Smith2
1Queensland University of Technology (QUT), Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia; Bond University, Faculty of Health Sciences and Medicine, 15 University Drive, Robina, Queensland 4226, Australia.
Insights
Genetic analysis of cerebral small vessel diseases (CSVDs) revealed Collagen type IV gene mutations in NOTCH3-negative individuals. This expands the genetic understanding of CSVDs and suggests broader genetic screening for improved diagnosis.
Area of Science:
- Neurogenetics
- Vascular Neurology
- Molecular Genetics
Background:
- Cerebral small vessel diseases (CSVDs) impact brain vasculature, leading to stroke and dementia.
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a common monogenic CSVD, is primarily linked to NOTCH3 mutations.
- A significant portion of clinically suspected CADASIL cases lack pathogenic NOTCH3 mutations, suggesting other genetic factors.
Purpose of the Study:
- To investigate alternative monogenic causes for CSVDs presenting with a CADASIL-like phenotype.
- To identify novel genetic mutations responsible for monogenic CSVDs in patients negative for NOTCH3 mutations.
Main Methods:
- Whole exome sequencing was performed on 50 individuals with suspected CADASIL but no NOTCH3 mutations.
- Targeted analysis was applied to screen for all known monogenic causes of CSVD.
Main Results:
- Three individuals were found to have mutations in Collagen type IV genes.
- These Collagen type IV mutations are likely causative of the CSVD phenotype in the identified individuals.
Conclusions:
- Broader genetic screening for all monogenic CSVDs is recommended when a single form is suspected, potentially improving diagnostic yield.
- The majority of NOTCH3-negative CSVD cases remain genetically unexplained, highlighting the need for further research to identify novel genetic contributors to CSVD.
Background And Aims:
Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3. We hypothesise that other monogenic causes of CSVD may be causing a CADASIL-like CSVD phenotype.
Methods:
To test this, we performed whole exome sequencing for 50 individuals suspected of having CADASIL, but did not exhibit a disease-causing mutation in NOTCH3, and applied targeted analysis of all monogenic forms of CSVD.
Results:
This analysis identified three mutations affecting the Collagen type IV genes in three individuals likely to be causative of CSVD.
Conclusions:
This suggests that screening for all monogenic forms of CSVD when one monogenic form is clinically suspected may improve diagnosis in clinically suspected monogenic CSVD. However, despite these findings, the majority of NOTCH3 negative CSVD cases did not have candidate mutations in known CSVD genes, suggesting that additional genetic factors contributing to the disease are yet to be identified.
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