Rare X-Linked Hypohidrotic Ectodermal Dysplasia in Females Associated with Ectodysplasin-A Variants and the X-Chromosome Inactivation Pattern

Abstract

The goal of this study was to identify the pathogenic gene variants in female patients with severe X-linked hypohidrotic ectodermal dysplasia (XLHED). Whole-exome sequencing (WES) and Sanger sequencing were used to screen for the pathogenic gene variants. The harmfulness of these variations was predicted by bioinformatics. Then, skewed X-chromosome inactivation (XCI) was measured by PCR analysis of the CAG repeat region in the human androgen receptor (AR) gene in peripheral blood cells. Two novel Ectodysplasin-A (EDA) heterozygous variants (c.588_606del19bp and c.837G>A) and one heterozygous variant (c.1045G>A, rs132630317) were identified in the three female XLHED patients. The bioinformatics analysis showed that these variants might be pathogenic. The tertiary structure analysis showed that these variants could cause structural damage to EDA proteins. Analysis of the skewed X-chromosome inactivation revealed that extreme skewed X-chromosome inactivation was found in patient #35 (98:2), whereas it was comparatively moderate in patients #347 and #204 (21:79 and 30:70). Our results broaden the variation spectrum of EDA and the phenotype spectrum of XLHED, which could help with clinical diagnosis, treatment, and genetic counseling.

Detection of an EDA mutation causing hypohidrotic ectodermal dysplasia in a Vietnamese patient

“…In 2004, a separate study in Korea also identified the mutation in a male proband, while the other members of this family were homozygous for the normal allele (Na et al, 2004). Interestingly, the variant c.1045G>A (p.A349T) was found to cause XLHED in a Chinese female carrier who exhibited XLHED traits such as lack of teeth, sparse eyebrows, hypohidrosis, and some other facial abnormalities (Haochen Liu et al, 2022). This female patient was determined to have significant skewed X-chromosome inactivation (XCI) with a ratio of 98:2.…”

“…This female patient was determined to have significant skewed X-chromosome inactivation (XCI) with a ratio of 98:2. However, the particular mechanism of skewed XCI to cause XLHED in female patients was not clear, as its consequences vary among different female carriers (Haochen Liu et al, 2022). Since the variant c.1045G>A (p.A349T) has been detected recurrently in several distinct patients with different ethnicities, it might be a mutational hot spot.…”