ABSTRACT NUMBER: ESOC2026A2462 YIELD OF NEXT-GENERATION SEQUENCING IN SUSPECTED GENETIC SMALL CEREBRAL VESSEL DISEASE PATIENTS WITHOUT CADASIL

Abstract Background and aims Although the genetic causes of cerebral small vessel disease (CSVD) are well established, routine practice usually tests only for NOTCH3 mutations in CADASIL. If the result is negative, further genetic evaluation is often not pursued. We aimed to assess the practical utility of next-generation sequencing (NGS) and to determine whether its use may already be meaningful in real-world practice. Methods Patients younger than 70 years were eligible if they had a family history of Mendelian inheritance, or clinical suspicion of a connective tissue disorder (ocular, renal, or skin involvement), and MRI evidence of CSVD according to STRIVE in the absence of relevant cardiovascular risk. All patients were first screened for NOTCH3 mutations. In the case of a negativity, NGS was performed using a targeted neurovascular panel analyzing 698 genes. Results Sixty-seven patients were included. CADASIL was identified in 8 (11.9%), with a mean age of 55.1 ± 13.7 years. The remaining 59 (88.1%) underwent NGS (mean age 57.7 ± 14.2 years). In the total cohort, NGS was negative in 42 (62.7%), pathogenic variants were identified in 10 (14.9%) in genes COL4A2 (3×), COL4A1 (2×), COL4A5, GLA, RNF213, RYR1 (2×), CSF1R, FBN2, and variants of uncertain significance (VUS) in 7 (10.4%) in genes COL2A1, NPC1, THSD1, APP, SERPINA1, FOXF2, ENG. Neither age, risk factors, nor Fazekas score differed significantly between genetic subgroups. Conclusions Genetic testing revealed a substantial number of pathogenic variants. It enabled initiation of Fabry disease–specific therapy and provided additional prognostic information for patients and their relatives. Conflict of interest Nothing to disclose.