Investigating diagnostic sequencing techniques for CADASIL diagnosis.
P J Dunn1, N Maksemous1, R A Smith1
1Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
Human Genomics
|January 10, 2020
Summary
Next-generation sequencing (NGS) panels significantly improve the detection of NOTCH3 gene mutations for diagnosing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare small vessel disease.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease.
- NOTCH3 gene mutations are the primary cause of CADASIL.
- Genetic diagnostic testing for CADASIL has evolved over time.
Purpose of the Study:
- To evaluate the diagnostic efficacy of different genetic sequencing technologies for CADASIL.
- To compare Sanger sequencing, targeted next-generation sequencing (NGS) panels, and whole exome sequencing (WES) for NOTCH3 mutation detection.
- To analyze mutation detection rates and characteristics over a long period.
Main Methods:
- Analysis of 680 patient samples and 764 genetic tests.
- Utilized Sanger sequencing, a targeted NGS gene panel (including NOTCH3 exons), and WES.
- Stratified mutation data by detection method, exon number, pathogenicity, and novelty.
Main Results:
- Overall mutation detection rate was 14.7% (100/680 patients).
- NGS custom panel achieved a higher mutation detection rate (15.8%) compared to Sanger sequencing (10.8%).
- WES identified a likely non-NOTCH3 pathogenic variant.
Conclusions:
- Next-generation sequencing (NGS) technologies, particularly custom panels, enhance the diagnostic yield for NOTCH3 mutations in CADASIL.
- The study highlights the evolution and improvement of genetic testing methodologies for CADASIL.
- Accurate genetic diagnosis is crucial for understanding and managing CADASIL.
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