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Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
X连锁多汗性外胚层发育不良（XLHED），一种罕见的遗传性疾病,影响外胚层衍生物的正常发育，比如头发，皮肤,牙齿,和汗腺。它是由EDA基因的致病变体引起的，并由三联症定义。牙齿过少或无牙齿，以及可能导致危及生命的高热的低汗症或无汗症。尽管女性携带者受到的影响不如男性患者严重，他们表现出症状，也是,具有高表型变异性。这项研究旨在阐明具有相同EDA基因型的女性XLHED患者的表型差异是否可以通过偏离X染色体失活（XI）模式来解释。
六个家庭,每个由具有相同EDA变体的两个姐妹及其父母组成（母亲或父亲是变体的携带者），参与了这项研究。与XLHED相关的数据，如出汗能力，牙齿状况,面部畸形,和皮肤问题进行了评估。我们通过人类雄激素受体测定确定了女性外周血白细胞中的个体XI模式，并将结果与表型特征进行了比较。
致病变异无法解释受影响女性中惊人的家族间和家族内症状变异性。我们的队列显示，外周血白细胞中非随机XI的发生率没有高于普通女性人群。此外，偏向突变等位基因的XI模式与更严重的表型无关。
我们在女性XLHED患者中没有发现优先XI的证据，并且XLHED相关表型特征和XI模式之间没有明显的相关性。表型变异似乎是由其他遗传或表观遗传因素引起的。
六个家庭,每个由具有相同EDA变体的两个姐妹及其父母组成（母亲或父亲是变体的携带者），参与了这项研究。与XLHED相关的数据，如出汗能力，牙齿状况,面部畸形,和皮肤问题进行了评估。我们通过人类雄激素受体测定确定了女性外周血白细胞中的个体XI模式，并将结果与表型特征进行了比较。
致病变异无法解释受影响女性中惊人的家族间和家族内症状变异性。我们的队列显示，外周血白细胞中非随机XI的发生率没有高于普通女性人群。此外，偏向突变等位基因的XI模式与更严重的表型无关。
我们在女性XLHED患者中没有发现优先XI的证据，并且XLHED相关表型特征和XI模式之间没有明显的相关性。表型变异似乎是由其他遗传或表观遗传因素引起的。
