Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with Cutis Laxa

Abstract Background Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and sagging in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. Methods In this study, we reported a case of a Han-Chinese male baby with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the new variant, and their parents were verified by sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. Results The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the baby carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of ATP6V0A2 gene. Conclusions In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. Few non-canonical splicing variants of ATP6V0A2 gene were reported in the past, and this variant expands the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the evidence level of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.