Reanalysis and Reclassification of UBA2 Variants in Patient with Syndactyly, Polydactyly, Aplasia Cutis Congenita and Other Anomalies Reveals Diagnosis

Abstract

Aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES) is known to cause by heterozygous mutation in the UBA2 gene. In this report we present the case of 7-year-old male with cutis aplasia, syndactyly, pre-axial polydactyly, and severe complex hypospadias. The exome sequencing identified a heterozygous frameshift variant [c.52_58dupGGCCGGG p.(Val20Gfs31)] in UBA2 gene. This variant is absent in gnomAD and has been predicted to be pathogenic by various as insilico tools. Following enrollment of the patient at Undiagnosed Rare Disease Clinic (URDC) this frameshift variant [c.52_58dupGGCCGGG p.(Val20Gfs31)] was reclassified as a pathogenic from Variant of unknown significance (VUS) according to ACMG guidelines. The variant classification affects the patient diagnosis, precision therapy and family screening. In this study, we highlighted the importance of reanalysis of genetic data for reclassification of variant from VUS to pathogenic in unsolved cases.