Table2_Identification of five novel variants of ADAR1 in dyschromatosis symmetrica hereditaria by next-generation sequencing.xlsx

BackgroundDyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant inherited pigmentary dermatosis characterized by a mixture of hyperpigmented and hypopigmented freckles on the dorsal aspect of the distal extremities. To date, pathogenic mutations causing DSH have been identified in the adenosine deaminase acting on RNA1 gene (ADAR1), which is mapped to chromosome 1q21.ObjectiveThe present study aimed to investigate the underlying pathological mechanism in 14 patients with DSH from five unrelated Chinese families. Next-generation sequencing (NGS) and direct sequencing were performed on a proband with DSH to identify causative mutations. All coding, adjacent intronic, and 5′- and 3′-untranslated regions of ADAR1 were screened, and variants were identified.ResultThese mutations consisted of three missense mutations (NM_001025107: c.716G>A, NM_001111.5: c.3384G>C, and NM_001111.5: c.3385T>G), one nonsense mutation (NM_001111.5:c.511G>T), and one splice-site mutation (NM_001111.5: c.2080-1G>T) located in exon 2, exon 14, and the adjacent intronic region according to recommended Human Genome Variation Society (HGVS) nomenclature. Moreover, using polymerase chain reaction and Sanger sequencing, we identified five novel ADAR1 variants, which can be predicted to be pathogenic by in silico genome sequence analysis. Among the mutations, the missense mutations had no significant effect on the spatial structure of the protein, while the stop codon introduced by the nonsense mutation truncated the protein.ConclusionOur results highlighted that the advent of NGS has facilitated high-throughput screening for the identification of disease-causing mutations with high accuracy, stability, and specificity. Five novel genetic mutations were found in five unrelated families, thereby extending the pathogenic mutational spectrum of ADAR1 in DSH and providing new insights into this complex genetic disorder.