X-chromosomal inactivation patterns in women with Fabry disease

Mol Genet Genomic Med. 2022 Sep;10(9):e2029. doi: 10.1002/mgg3.2029.

PMID: 35971858

Laura Wagenhäuser, Vanessa Rickert, Claudia Sommer

Highlights: This study investigates X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in women with Fabry disease (FD).

Abstract

Background: Women may experience severe symptoms even though Fabry disease (FD) is an X-linked lysosomal storage disease brought on by mutations in the α-galactosidase A gene (GLA). X-chromosomal inactivation patterns (XCI) were investigated as a possible factor in FD women's symptom severity.

Patients and methods: The methylation status of the androgen receptor gene was used to perform XCI analysis on mouth epithelial cells, venous blood, and skin fibroblasts from 95 women with mutations in GLA (n = 18 with variants of uncertain significance) and 50 related men. Comparing samples from relatives allowed researchers to pinpoint the mutant X-chromosome. Patients underwent extensive clinical phenotyping of symptom intensity and genotype categorization.

Results: 43/95 (45%) women carried mutations categorized as classic. In 6/87 (7%) oral epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples, the XCI pattern was skewed (i.e., 75:25% distribution). When clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels were stratified for X-chromosomal skewing and the status of the mutant X chromosome's activity, no intergroup variations were visible.

Conclusions: When examined in biomaterial that is not directly impacted by FD, X-inactivation patterns alone do not consistently reflect the clinical profile of women with FD. However, blood frequently exhibits skewing of XCI patterns, despite the fact that XCI patterns may differ between tissues.

Keywords: Fabry disease, Fabry genotype, Fabry phenotype, X-chromosomal inactivation, female Fabry patients