Abstract Background and aims Stroke in young patients is frequently unexplained by conventional cardiovascular risk factors, suggesting a genetic contribution. Homozygous or compound heterozygous pathogenic variants in the ABCC6 gene cause pseudoxanthoma elasticum (PXE) and are associated with vascular calcification and ischemic stroke. The role of heterozygous ABCC6 variants in familial ischemic stroke remains unclear. This study aims to explore the potential association between heterozygous pathogenic ABCC6 variants and familial ischemic stroke, and to describe clinical characteristics and stroke subtypes among ABCC6 variant carriers. Methods This clinical–genetic case study utilized data from the Young Stroke in Skåne database, including 180 patients with ischemic stroke before age 56 (2021–2024). Five index patients carrying pathogenic or likely pathogenic ABCC6 variants were identified. Whole-genome sequencing and an extended stroke gene panel excluded alternative monogenic stroke causes. Clinical data were collected, including cardiovascular risk factors, PXE-related manifestations, cognitive screening (Montreal Cognitive Assessment, MoCA), and ischemic stroke subtypes (Trial of Org 10172 in Acute Stroke Treatment, TOAST criteria). Pedigree-based co-segregation analysis was performed in affected families. Results Six possible disease-causing ABCC6 variant carriers with ischemic stroke were identified. The mean age at stroke onset was 45.8 years. Stroke subtypes included small vessel disease (n=2), cardioembolic stroke (n=2), and cryptogenic/complex risk profile (n=2). Clinical presentations were heterogeneous but consistently characterized by early-onset ischemic stroke. These findings suggest a possible association between heterozygous pathogenic ABCC6 variants and familial early-onset ischemic stroke. Larger, well-characterized cohorts are required to confirm this association and clarify the role of ABCC6 in stroke susceptibility. Conflict of interest Anastasia Janssen: nothing to disclose.
Janssen et al. (Fri,) studied this question.