Hypohidrotic Ectodermal Dysplasia (HED) is a rare heterogeneous genetic disorder due to deficient development of multiple ectodermal structures including hair, sweat glands and teeth. X-linked subtype (XHED) is the most common, with an incidence of 1 /50.000- 100.000 males, associated to EDA gene (Xq12-q13.1; MIM 300451) mutations; the dominant and recessive subtypes affect EDAR (2q13MIM 604095) and EDARADD (1q42.3; MIM 606603) genes. It has been also described cases with WNT10A gene (2q35; MIM 606268) mutations. Our aim was to find out the mutational spectrum in our HED population. 

A cohort of 55 HED patients was clinically evaluated and genotyping of EDA (NM_001399.4), EDAR (NM_022336.3), EDARADD (MN_145861.2) and WNT10A genes (MN_025216.2) was performed by Sanger sequencing.  Multiplex Ligation-dependent Probe Amplification assay (MLPA) (salsa P-183-C1 probemix) was carried out when a normal sequencing result was obtained. Pathogenic variants were established by family segregation studies and in silico prediction analysis with softwares the Provan and Polyphen2. 

At least a pathogenic mutation was detected in 70.9% (39/55) of the patients. Of these, 82% had mutations in EDA, 7.6% in EDAR, 7.6% in EDARADD and 2.5% in WNT10A gene.
Most of the variants were inherited (71.8%) following X-linked dominant pattern (82%) or autosomal pattern (15.4%). There was only a compound heterozygous variant following a recessive inherited pattern affecting EDAR. Data shows a high mutational variability: deletion of complete EDA gene (1) and deletion of exon 1 EDA (2) detected by MLPA, missense (22), nonsense (4) and small indels (4), frameshift indels (5) and intronic variants (2). 42.5% (17/40) of observed variants had not been described before in the genomic databases, in these cases the in silico predictions and segregation studies determined their pathogenicity.

A variant in EDARADD (p.Ser103Phe) was recurrent in three patients, one of them having another heterozygous EDA mutation. In the other two cases no additional variants were detected so mutations affecting other genes of the EDA signaling pathway not included in this study could be responsible for the HED phenotype.

Most mutations in our population are private and located in EDA gene, associated to XHED, more frequently in exons 1, 5 and 8-9, constituting hot spots. Most mutations are inherited, underlying the importance of the family study for proper genetic counselling. On the other hand, our study makes clear the need to expand the number of genes to be studied in this heterogeneous disease.

Mutational spectrum in 39 Spanish patients with Hypohidrotic Ectodermal Dysplasia