# ABCC6 Heterozygosity as Genetic Predisposition to Cerebrovascular Disease Across Ages

## TL;DR

This study shows that having one copy of a harmful ABCC6 gene variant increases the risk of cerebrovascular disease, with different effects in children and adults.

## Contribution

The study identifies age-dependent differences in cerebrovascular disease phenotypes associated with monoallelic and biallelic ABCC6 variants.

## Key findings

- 11.2% of patients had causative ABCC6 gene variants, with distinct disease patterns based on variant type.
- Biallelic ABCC6 variants were linked to severe vasculopathy and early ischemic events.
- Monoallelic variants were associated with microvascular disease and CSVD features.

## Abstract

Background: Heterozygosity for pathogenic variants in the ABCC6 gene has been associated with an increased incidence of cerebrovascular diseases. This study aims to characterize the prevalence and clinical and neuroradiological phenotypes associated with monoallelic and biallelic ABCC6 variants in pediatric and adult patients presenting with arterial ischemic stroke or cerebral small vessel disease (CSVD). Methods: We conducted a retrospective observational study on 143 consecutive patients (48 pediatric, 24 juvenile, 71 adult) diagnosed with ischemic stroke or CSVD of unknown etiology. Clinical and neuroradiological data were collected and analyzed in relation to the identified genetic variants through next-generation sequencing. Results: Among the patients, 16 (11.2%) tested positive for causative variants in the ABCC6 gene, with 11 subjects carrying monoallelic variants and 5 carrying biallelic variants. Patients with biallelic variants exhibited severe and complex vasculopathy, with a high incidence of early ischemic events. In contrast, monoallelic carriers predominantly presented with microvascular disease manifestations, including lacunar strokes and signs of CSVD. Conclusions: The results suggest a significant age-dependent phenotypic divergence in patients with ABCC6 variants, highlighting the impact of heterozygosity on cerebrovascular health. Identifying these variants may enhance risk stratification and inform management strategies in patients with traditional vascular risk factors.