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

BACKGROUND AND OBJECTIVES

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.

METHODS

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

RESULTS

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 p.R544C variants, 12 with variants in EGFr 7-34 outside the p.R544C hotspot, 11 with variants in EGFr 1-6, 9 with , 5 with , 2 with , and 1 with a 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 pathogenic variants had similar ages at genetic diagnosis, ages at stroke, and WMH severity compared with those with pathogenic variants in EGFr 7-34. However, they had a later age at onset and milder severity compared with those with pathogenic variants in EGFr 1-6. Anterior temporal WMH involvement was most pronounced in patients with EGFr 1-6 (82%), less in EGFr 7-34 (33%), and absent in those with pathogenic variants.

DISCUSSION

Monogenic disease-causing variants are relatively common in Taiwanese patients with SVD, particularly the p.R544C variants. variants exhibited similar clinical and imaging features to 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.