Wang Yupei, Zhang Chuan, Zhou Bingbo, Hui Ling, Zheng Lei, Chen Xue, Wang Shifan, Yang Lan, Hao Shengju, Zhang Qinghua
Medical Genetics Center, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, China.
Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou, China.
Front Genet. 2022 Jul 6;13:916340. doi: 10.3389/fgene.2022.916340. eCollection 2022.
Ectodysplasin A (EDA) variations are major pathogenic factors for hypohidrotic ectodermal dysplasia (HED), the most common form of ectodermal dysplasia (ED), characterized by hypotrichosis, hypohidrosis, hypodontia, and other oral features. 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 analysis. De novo deletion was confirmed by chromosomal microarray analysis. Three variants (c.396 + 1 G > C, c.171-173 del GTT, and exon 1 deletion) were identified, all affecting exon 1 of the 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 . 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. Investigating the clinical and molecular characteristics of these variations broadens our understanding of gene variants, supporting clinical diagnosis, genetic counseling, and prenatal diagnosis of HED.
外胚层发育不良蛋白A（EDA）变异是少汗型外胚层发育不良（HED）的主要致病因素，HED是最常见的外胚层发育不良（ED）形式，其特征为毛发稀少、少汗、牙齿发育不全及其他口腔特征。通过全外显子测序检测了3个HED家系中的分子遗传学缺陷，并通过桑格测序或多重连接依赖探针扩增进行了确认。通过EDA小基因分析进一步验证了剪接变异的影响。通过染色体微阵列分析确认了新生缺失。鉴定出3种变异（c.396 + 1 G > C、c.171-173 del GTT和外显子1缺失），均影响该基因的外显子1。变异c.396 + 1 G > C和c.171-173 del GTT为首次鉴定。对剪接变异（c.396 + 1 G > C）的小基因分析显示，EDA-A1转录本延长，在第1内含子起始处包含额外的699 bp，代表功能性隐蔽剪接位点的形成。结合染色体微阵列分析和全外显子测序结果，缺失变异超过87 kb。3种变异预计会不同程度地影响蛋白质功能，并导致具有不同表型的X连锁HED。对这些变异的临床和分子特征进行研究，拓宽了我们对基因变异的认识，为HED的临床诊断、遗传咨询和产前诊断提供了支持。
