PRJNA503870
A CIB1 Splice-site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis
Epidermodysplasia verruciformis (EV), an autosomal recessive genodermatosis, manifests typically with flat warts triggered by persistent infection by human papilloma viruses of the beta-genus (beta-HPVs). Many patients develop later in life non-melanoma skin cancers on the areas of UV exposure. EV is considered typical when the HPV-driven skin lesions are an isolated clinical feature with no evidence of compromised T-cell mediated immunity. The typical forms of EV were initially shown to result from loss-of-function mutations in TMC6/EVER1 and TMC8/EVER2. We recently showed that mutations in a third gene, CIB1, can be identified in some patients with typical EV, and that the CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to beta-HVPs. Here, we characterized a consanguineous family with three similarly affected siblings with EV. The diagnosis was based on clinical findings, histopathology, HPV genotyping and immunophenotyping. Whole exome sequencing, assisted by homozygosity mapping, identified a CIB1 splice site mutation, c.52-2A>G, which was shown by RNA-seq and differential gene expression heatmap analysis to result in complex aberrant splicing and nonsense-mediated mRNA decay. Haplotype analysis using single nucleotide polymorphism markers surrounding the CIB1 locus identified a 2.2 Mb region of homozygosity in this family shared with four individuals in another family previously reported with the same mutation, providing evidence of founder effect. Collectively, these studies confirm that bi-allelic CIB1 mutations, including recurrent splice site mutations, can underlie typical EV.