AUTHOR=Wang Yupei , Zhang Chuan , Zhou Bingbo , Hui Ling , Zheng Lei , Chen Xue , Wang Shifan , Yang Lan , Hao Shengju , Zhang Qinghua 

TITLE=Three Variants Affecting Exon 1 of Ectodysplasin A Cause X-Linked Hypohidrotic Ectodermal Dysplasia: Clinical and Molecular Characteristics

JOURNAL=Frontiers in Genetics

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.916340

DOI=10.3389/fgene.2022.916340

ISSN=1664-8021

ABSTRACT=Background
Ectodysplasin A (EDA) variations are major pathogenic factors for hypohidrotic ectodermal dysplasia (HED), the most common form of ectodysplasin (ED), characterized by hypotrichosis, hypohidrosis, hypodontia, and other oral features. 
Methods 
Molecular genetic defects in three HED families were detected by whole-exome sequencing and confirmed by Sanger sequencing or multiplex ligation-dependent probe amplification. The effect of splicing variant was further verified by EDA minigene in vitro analysis. De novo deletion was confirmed by chromosomal microarray analysis. 
Results  
Three variants (c.396+1 G>C, c.171-173 del GTT, and exon 1 deletion) were identified, all affecting exon 1 of the EDA gene. Variants c.396+1 G>C and c.171-173 del GTT were first identified. Minigene analysis of the splicing variant (c.396+1 G>C) displayed a prolonged EDA-A1 transcript containing extra 699 bp at the start of intron 1, representing a functional cryptic splice site formation in vitro. Combining the results of chromosomal microarray analysis and whole-exome sequencing, the  deletion variant was over 87 kb. Three variants were predicted to affect protein function to differing degrees, and were responsible for X-linked HED with varying phenotype.
Conclusion
Investigating the clinical and molecular characteristics of these variations broadens our understanding of EDA gene variants, supporting clinical diagnosis, genetic counseling, and prenatal diagnosis of HED.