Functional and clinical analysis of five EDA variants associated with ectodermal dysplasia but with a hard-to-predict significance

Abstract

Deficiency of ectodysplasin A1 (EDA1) due to variants of the gene EDA causes X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic condition characterized by abnormal development of ectodermal structures. XLHED is defined by the triad of hypotrichosis, hypo- or anhidrosis, and hypo- or anodontia. Anhidrosis may lead to life-threatening hyperthermia. A definite genetic diagnosis is, thus, important for the patients’ management and amenability to a novel prenatal treatment option. Here, we describe five familial EDA variants segregating with the disease in three families, for which different prediction tools yielded discordant results with respect to their significance. Functional properties in vitro and levels of circulating serum EDA were compared with phenotypic data on skin, hair, eyes, teeth, and sweat glands. EDA1-Gly176Val, although associated with relevant hypohidrosis, still bound to the EDA receptor (EDAR). Subjects with EDA1-Pro389LeufsX27, -Ter392GlnfsX30, -Ser125Cys, and an EDA1 splice variant (c.924+7A > G) showed complete absence of pilocarpine-induced sweating. EDA1-Pro389LeufsX27 was incapable of binding to EDAR and undetectable in serum. EDA1-Ter392GlnfsX30, produced in much lower amounts than wild-type EDA1, could still bind to EDAR, and so did EDA1-Ser125Cys that was, however, undetectable in serum. The EDA splice variant c.924+7A > G resulted experimentally in a mix of wild-type EDA1 and EDA molecules truncated in the middle of the receptor-binding domain, with reduced EDA serum concentration. Thus, in vitro assays reflected the clinical phenotype in two of these difficult cases, but underestimated it in three others. Absence of circulating EDA seems to predict the full-blown phenotype of XLHED, while residual EDA levels may also be found in anhidrotic patients. This indicates that unborn subjects carrying variants of uncertain significance could benefit from an upcoming prenatal medical treatment even if circulating EDA levels or tests in vitro suggest residual EDA1 activity.

Canine noninflammatory alopecia: An approach to its classification and a diagnostic aid

“…Some variants lead to a complete loss of the protein function and a severe clinical picture, whereas other variants are associated with residual EDA activity and milder phenotypes. 15,46…”

Extended Overview of Ocular Phenotype with Recent Advances in Hypohidrotic Ectodermal Dysplasia

“…A recent study by Gökdere et al aiming to further elucidate a correlation between the genotype and phenotype of XLHED through in vitro assays concluded that the absence of circulating EDA levels is associated with a null variant in the EDA gene. On the other hand, the presence of circulating EDA does not rule out ED; this is likely explained by the fact that normal levels of a functionally impaired protein can lead to a similar ED phenotype [ 11 ].…”

Dental implants survival rates among ectodermal dysplasia patients: aggregation and synthesis of literature data

“…Due to the previous literature data prevalence of clinically established or clinically possible diagnosis of ectodermal dysplasia (ED) represented by 21.9 cases for 100000 overall, while molecular diagnostics cut off this level to the 1.6 cases per 100000 [1,2,3]. Nowadays nearly 189 pathological conditions may be initially categorized as ectodermal dysplasia cases [4]. Dental changes have been noted among 79% cases of clinically established ED, and among 52% of ED cases, which has been molecularly approved [2,3,5] (Figure 1).…”