Clinical and genetic study of a family with epidermolysis bullosa simplex caused by a novel KRT5 gene mutation c.987C>G (p.Asn329Lys).

Abstract

This study investigated the association between the novel KRT5 gene mutation c.987C>G (p.Asn329Lys) and the clinical phenotype of epidermolysis bullosa simplex (EBS), to provide a basis for the molecular diagnosis and genetic counseling of EBS. Clinical data were collected from a 20-year-old female patient. Whole-exome sequencing was performed on the proband, 5 affected family members, and 2 healthy family members, with mutations verified by Sanger sequencing. Functional prediction was conducted using SIFT, PolyPhen-2, and MutationTaster, while conservation analysis was performed using ConSurf and NCBI CDD databases. The pathogenicity of the mutation was evaluated according to the 2015 ACMG guidelines. Results showed that the proband and all affected family members carried the heterozygous KRT5 gene mutation c.987C>G (p.Asn329Lys), while healthy members did not, consistent with autosomal dominant co-segregation. This mutation was not recorded in databases such as gnomAD, indicating it is a novel mutation. Functional prediction showed SIFT score 0.00 (damaging), PolyPhen-2 score 1.000 (PROBABLY DAMAGING), and MutationTaster classification as "Deleterious". Conservation analysis confirmed that the 329th amino acid is located in the highly conserved Filament domain (ConSurf score 0.92, CDD E-value = 1.04e- 158). The ACMG classification determined it as "Pathogenic". Affected family members exhibited a mild phenotype characterized by "friction-induced blisters, seasonal dependence, and scarless healing". The KRT5 gene mutation c.987C>G (p.Asn329Lys) is a novel pathogenic mutation for EBS. Its unique phenotype enriches the genotype-phenotype spectrum of EBS and has important reference value for clinical practice.