A Homozygous Nonsense Variant in <i>UVSSA</i> Causes UV-sensitive Syndrome from Very Large Kindred: The First Report from Iran

Abstract

Background: Recessive disruptive mutations in nucleotide excision repair genes are responsible for a wide range of cutaneous photosensitivity and, in some cases, are associated with multi-system involvement. The heterogeneous nature of these conditions makes next-generation sequencing the method of choice to detect disease-causing variants. Materials and Methods: A patient from a large multiplex inbred Iranian kindred with several individuals suffering from skin sun-sensitive manifestations underwent complete clinical and molecular evaluations. Whole exome sequencing (WES) was performed on the genomic sample of the proband, followed by bioinformatics analysis. Subsequently, co-segregation of the candidate variant with the condition was performed by Sanger sequencing. Results: A rare homozygous nonsense variant, c.1040G>A (p. Trp347*), was identified in the UVSSA gene, resulting in UV-sensitive syndrome (UVSS) complementation group A. The global minor allele frequency of the variant is < 0.001 in population databases. Tryptophan 347 residue is conserved among mammalians and vertebrates, and the null variant is believed to lead to a truncated protein with cellular mislocalization. Conclusions: Here, we report the first genetic diagnosis of UVSS-A in Iran via the successful application of Next-generation sequencing, which expands our understanding of the molecular pathogenesis of this condition.