Prevalence and Characteristics of Pathogenic Variants in Taiwanese Patients With Cerebral Small Vessel Disease

The Taiwan-Associated Genetic and Non-genetic Small Vessel Disease (TAG-SVD) cohort prospectively enrolls patients with cerebral small vessel disease (SVD). The aim of this study was to determine the prevalence and characteristics of monogenic SVD in patients within the TAG-SVD cohort.

All patients in the TAG-SVD cohort underwent initial screening for NOTCH3 p.R544C variant, which is the hotspot disease-causing variant in Taiwan. Those who tested negative for NOTCH3 p.R544C variant underwent next-generation sequencing targeting 5 candidate SVD genes: NOTCH3, HTRA1, GLA, TREX1, and COL4A1. Clinical and neuroimaging features were compared between the genetic and nongenetic groups, as well as between specific pathogenic variants in NOTCH3 and HTRA1.

A total of 1,086 patients (mean age 62.9 ± 12.4 years, 61% male) were enrolled. Disease-causing variants in the candidate genes were identified in 284 patients (26.2%), including 244 with the NOTCH3 p.R544C variants, 12 with NOTCH3 variants in EGFr 7-34 outside the p.R544C hotspot, 11 with NOTCH3 variants in EGFr 1-6, 9 with HTRA1, 5 with TREX1, 2 with COL4A1, and 1 with a GLA pathogenic variant. Compared with those with nongenetic SVD, individuals with monogenic SVD were more likely to be female, exhibited a higher familial stroke history, had lower rates of hypertension and diabetes, and experienced fewer previous strokes. They also displayed more severe white matter hyperintensity (WMH) and a higher prevalence of anterior temporal and external capsule WMH involvement on MRI. Patients with HTRA1 pathogenic variants had similar ages at genetic diagnosis, ages at stroke, and WMH severity compared with those with NOTCH3 pathogenic variants in EGFr 7-34. However, they had a later age at onset and milder severity compared with those with NOTCH3 pathogenic variants in EGFr 1-6. Anterior temporal WMH involvement was most pronounced in patients with NOTCH3 EGFr 1-6 (82%), less in NOTCH3 EGFr 7-34 (33%), and absent in those with HTRA1 pathogenic variants.

Monogenic disease-causing variants are relatively common in Taiwanese patients with SVD, particularly the NOTCH3 p.R544C variants. HTRA1 variants exhibited similar clinical and imaging features to NOTCH3 EGFr 7-34 variants, but without anterior temporal WMH involvement. These findings underscore the importance of genetic screening to understand SVD heterogeneity and guide personalized management.