Gene Panel Approach to Screen for Hereditary Cerebral Small Vessel Disease: A Proof-of-Concept Study

Area of Science:

• Neurology
• Genetics
• Medical Diagnostics

Background:

• Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia.
• Identifying patients with hereditary cSVD (hcSVD) is challenging due to poorly defined predictive algorithms.
• Selecting patients for genetic screening requires improved pre-screening methods.

Purpose of the Study:

• To evaluate the predictive performance of a phenotype-based algorithm for identifying patients with hcSVD.
• To assess the yield of a high-throughput gene panel in detecting clinically relevant genetic variants (CRGVs) in cSVD patients.
• To compare the prevalence of CRGVs and variants of unknown significance (VUSs) between high-probability and low-probability groups.

Main Methods:

• A phenotype-based algorithm was used to select patients for genetic screening.
• A high-throughput gene panel targeting 27 candidate genes associated with cSVD was employed.
• Patients were categorized into High-Probability Group (HPG) and Low-Probability Group (LPG) for molecular analysis.

Main Results:

• Among 65 probands, 16.9% had CRGVs or VUSs.
• Pathogenic CRGVs were found in 18.2% of the HPG (4/22 probands), with none in the LPG.
• VUSs were more frequent in the HPG (22.7%) compared to the LPG (4.6%).

Conclusions:

• The proposed pragmatic algorithm effectively identifies patients with a higher likelihood of harboring monogenic cSVD.
• This approach enhances the diagnostic yield for hereditary forms of cSVD.
• The findings support the use of phenotype-based algorithms to guide genetic testing in cSVD patients.