Mutational spectrum of EDA, EDAR, EDARADD, and WNT10A genes in the largest cohort of Russian patients with hypohidrotic ectodermal dysplasia.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) encompasses a group of rare genetic disorders affecting two or more ectodermal derivatives (hair, teeth, nails, certain glands). The condition can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner, with the majority of cases caused by mutations in the EDA, EDAR, EDARADD, and WNT10A genes. This study aimed to evaluate the distribution of pathogenic and likely pathogenic variants in 261 unrelated families affected by HED in the Russian Federation (comprising 455 patients in total) between 2007 and 2024. To achieve this objective, we employed Sanger sequencing, targeted gene panel sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and segregation analysis to clarify the pathogenicity of variants of uncertain significance. RESULTS: A total of 261 unrelated probands, comprising 196 males (75.1%) and 65 females (24.9%), were included. Pathogenic or likely pathogenic variants were identified in 183 probands (70.1%). The distribution of mutated genes was as follows: EDA (n = 155, 84.7%), WNT10A (n = 16, 8.8%), and EDAR (n = 12, 6.5%). No apparent pathogenic mutations were detected in EDARADD. Additionally, we report 46 novel causative variants for HED, along with recurrent mutations in the EDA, WNT10A, and EDAR genes. We also identified that 28.8% of all causative variants in EDA are de novo. CONCLUSION: This is the only molecular study conducted in the Russian population affected by HED and represents the largest HED cohort published to date globally. Our findings significantly expand the mutational spectrum of HED-causing genes and will aid in choosing an initial diagnostic approach for HED patients. Further studies using whole-genome sequencing (WGS) will help to identify other contributory genes in the remaining uncharacterized Russian patients with HED.