No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia

Abstract

Background X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns. Methods Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features. Results The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes. Conclusions We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.

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

“…It has been reported that the HED phenotype in EDA female carriers is not correlated with the XCI pattern [ 28 ]. Laura et al found that women with mild HED did not have higher non-randomized XCI ratios and that there was no significant correlation between tilted XI ratios and XLHED phenotypic expression levels [ 29 ]. In this study, patient #35 showed extremely skewed (98:2) XCI, and patients #347 and #204 showed moderately skewed (21:79 and 30:70) XCI.…”

Reproductive decision‐making by women with X‐linked hypohidrotic ectodermal dysplasia

“…A high degree of inter-and intrafamilial variability of symptoms among affected females has been observed. 24 Females are sometimes only recognized to be carriers of XLHED when they have siblings with the condition. 25 Sons of female carriers-if affected-are likely to show a more severe phenotype than their mothers.…”

“…Heterozygous females are usually not as severely affected by XLHED as hemizygous males. A high degree of inter‐ and intrafamilial variability of symptoms among affected females has been observed 24 . Females are sometimes only recognized to be carriers of XLHED when they have siblings with the condition 25 .…”

Clinical and molecular characterization of craniofrontonasal syndrome: new symptoms and novel pathogenic variants in the EFNB1 gene

“…Our finding, therefore, suggests that skewed X inactivation cannot account for the mild presentation of CFNS in one of our twin sisters and probably other mildly affected female individuals. Recently, another research group did not find evidence for preferential XCI or a distinct correlation between XCI ratios in a group of familial X-linked hypohidrotic ectodermal dysplasia patients showing variable disease manifestation [ 21 ]. Hence our result strengthens the above conclusion regarding the presence of additional yet undetected modifying factors resulting in discordant phenotype in X-linked disorders.…”