Ectodermal dysplasia, a rare congenital disease, is characterized by developmental defects in two or more ectodermal-derived appendages (hair, nails, sweat glands, and teeth) (Lucero Saá et al., 2020). Hypohidrotic ectodermal dysplasia and hidrotic ectodermal dysplasia are two forms of ectodermal dysplasia. The former is the most common type of ectodermal dysplasia, with a frequency of 7 per 100,000 births (Noriega-Juárez et al., 2020). It causes diminished or absent sweat glands, sparse hair, missing and/or malformed teeth, and nail abnormalities (Azar et al., 2016, Modi et al., 2021). The occurrence of ectodermal dysplasia endangers the physical and mental health of patients and health-related quality of life. However, the pathogenic mechanism of ectodermal dysplasia remains mostly unclear.

It has been reported that ectodermal dysplasia can be caused by mutations in ectoderm-related genes including WNT10A (OMIM 257980), EDA (OMIM 305100), EDAR (OMIM 224900), IKBKG (OMIM 300248), and TP63 (OMIM 604292) (Itin, 2014, Khan et al., 2020, Parveen et al., 2019). Genes of the signaling pathway of ectodermal development may contribute to the increased risk of ectodermal dysplasia (Diao et al., 2019). The growth and development of ectoderm have been discovered to be affected by several key signaling pathways at the phenotypic level including WNT, EDA/NF-KB, and TP63 signaling pathways (Wright et al., 2019). The heterozygous variants of TP63 are identified in different human developmental diseases including limb deformity, ectodermal dysplasia, and facial clefts (van Bokhoven & Brunner, 2002). As one of the p53 family members, TP63 is involved in epithelial cell proliferation and played an important role in epidermal morphogenesis (Kurinna et al., 2021, Mills et al., 1999, Viticchiè et al., 2015, Wang et al., 2021).

In this study, we identified the variant of TP63 associated with ectodermal dysplasia in a nuclear Han Chinese family. We further performed bioinformatics analysis to infer the effect of protein function. Additionally, based on three transcriptomics datasets and single-cell RNA-sequencing data, we revealed that TP63 was involved in the development of ectodermal appendages and may play an essential role in this process.