Uncovering a Diagnosis Through Reanalysis of UBA2 Variants in a Patient with Syndactyly, Polydactyly, and Aplasia Cutis Congenita: A Short Report and a Review of the Literature.

Background

Aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES) is caused by heterozygous variants in the UBA2 gene, with phenotypic heterogeneity encompassing a range of diverse skeletal, dermatological, and neurological features. Aims: The goal of our research was to suggest that pathogenic frameshift variant c.52_58dupGGCCGGG p.(Val20Gfs*31) could lead to the development of ACCES and also to review the literature to document phenotypic variability among individuals with UBA2 variants, providing further insights into this ultrarare syndrome. Methods and Result: We report a case of a 7-year-old male presenting with cutis aplasia congenita, syndactyly, preaxial polydactyly, and severe hypospadias. Exome sequencing (ES) identified a heterozygous frameshift variant c.52_58dupGGCCGGG p.(Val20Gfs*31) in the UBA2 gene. This variant is absent in gnomAD and is predicted to cause a premature stop codon with consequent protein truncation and/or nonsense-mediated decay. Initially classified as a variant of uncertain significance, this frameshift variant was reclassified as pathogenic following a comprehensive reassessment post-enrollment of the patient in the Undiagnosed Rare Disease Clinic of Indiana University School of Medicine.

Conclusion

This study illustrates the critical role of ongoing genomic data reevaluation, particularly in unsolved cases, where variant reclassification has the potential to impact diagnostic precision, targeted treatment planning, and family counseling. The clinical variability observed among reported cases, spanning mild to severe presentations, underscores the complexity of UBA2-related disorders. This variability suggests an interplay of genetic modifiers, epigenetic influences, and environmental factors, highlighting the need for further research into the mechanisms driving this heterogeneity.