Prognostic significance of X-сhromosome inactivation in female carriers of EDA mutations

Abstract

Introduction. Ectodermal dysplasia (ED) represents a heterogeneous group of genetic disorders associated with impaired development of ectodermal structures. The most common form is X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by mutations in the EDA gene, which encodes ectodysplasin A, a key protein involved in the development of ectodermal tissues. Due to the X-linked inheritance pattern, males are more frequently affected; however, female carriers may also exhibit clinical manifestations. The phenotypic variability in females has traditionally been attributed to skewed X-chromosome inactivation (XCI), though this hypothesis remains controversial.

Objective: The aim of this study was to analyze XCI patterns in female carriers of EDA mutations and assess their correlation with the severity of clinical manifestations.

Methods. The study was conducted on 47 female patients using methylation-sensitive PCR and analysis of repeats in the AR gene.

Results. The obtained data did not reveal a statistically significant correlation between the degree of XCI and the severity of HED symptoms (p = 0.277).

Conclusion. This study confirms that the analysis of XCI in blood is not a reliable predictor of disease severity in females with X-linked HED and, therefore, should not be recommended for diagnostic purposes or reclassification of variants of uncertain significance in the EDA gene.