关键词: 遗传性对称性色素异常症, 全外显子组测序ADAR基因, 新发变异

Abstract: Objective To analyze the clinical features and to identify the pathogenic variants in three Chinese families with dyschromatosis symmetrica hereditaria (DSH). Methods Clinical information and peripheral blood samples from three trio families with DSH were collected. The variants were detected by whole exome sequencing and then confirmed by Sanger sequencing. Pathogenicity of the variants was evaluated with a series of bioinformatic software. Results All the probands from the three Chinese families showed a mixture of pigmented and depigmented macules on the extremities. Three heterozygote single-nucleotide-variants, c.3546T＞G (p.Tyr1182*), c.2770T＞G (p.Tyr924Asp) and c.3116A＞C (p.Lys1039Thr), in the ADAR(NM_001111.5) gene were detected by WES in the three probands respectively. The first two variants were not present in the public databases such as gnomAD and HGMD, and the third one was previously reported in HGMD but not presented in the public databases. The relevant variants were undetectable in their parents of the three probands shown by Sanger sequencing, and were consequently regarded as de novo variants. These variants located in the highly conservative sites, all of which were located in the double-stranded RNA adenosine deaminase domain of the protein encoded by ADAR. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the nonsense variant, c.3546T＞G in ADAR, was categorized as a pathogenic variant (PVS1+PS2+PM2+PP3+PP4) and the missense variants, c.2770T＞G and c.3116A＞C in ADAR, were categorized as pathogenic variants (PS2+PM1+PM2+PP3+PP4) and (PS1+PS2+PM1+PM2+PP3+PP4), respectively. Conclusions Three de novo variants in ADAR, c.3546T＞G, c.2770T＞G and c.3116A＞C are probably the genetic pathogenesis of DSH in these three probands respectively, which enriched the genetic profile of ADAR.

Key words: dyschromatosis symmetrica hereditarian, whole exome sequencing, ADAR, de novo variants