Genetic analysis of a Chinese pedigree affected with Epidermolysis bullosa simplex due to a novel variant of KRT5 gene.
10.3760/cma.j.cn511374-20250310-00144
- Author:
Shaoguang LYU
1
,
2
;
Fang LIU
;
Zhifang DU
;
Kun WANG
;
Mengdi YANG
Author Information
1. Department of Neonatology, 980th Hospital of PLA Joint Logistic Support Force, Shijiazhuang, Hebei 050082, China. liufanglafy@
2. com.
- Publication Type:English Abstract
- MeSH:
Child;
Female;
Humans;
Infant;
Male;
China;
Epidermolysis Bullosa Simplex/genetics*;
Exome Sequencing;
Keratin-5/genetics*;
Mutation;
Pedigree;
Retrospective Studies;
East Asian People/genetics*
- From:
Chinese Journal of Medical Genetics
2025;42(10):1226-1231
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To investigate the clinical characteristics and genetic etiology of eight members from a pedigree affected with epidermolysis bullosa (EB).
METHODS:A girl presented with recurrent, unexplained blisters on the palmar and plantar skin for 8 years and sought medical care in October 2024 was enrolled as the study subject. A retrospective study was conducted to collect the child's clinical data, and a detailed medical history was taken for her family members. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was validated by Sanger sequencing. The pathogenicity of the candidate variants was classified in accordance with the Standards and Guidelines for the Interpretation of Sequence Variants issued by the American College of Medical Genetics and Genomics (ACMG, hereinafter referred to as the "ACMG Guidelines"). This study was approved by the Medical Ethics Committee of the 980th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army (Ethics No.: 2019-KY-01).
RESULTS:The proband was an 8-year-and-4-month-old female. Four months after birth, she had developed recurrent blisters on the palmar and plantar skin without obvious triggers, accompanied by significant pain. Symptoms were more severe in summer and slightly relieved in winter. Although symptomatic treatment could alleviate the symptoms, she was unable to participate in physical activities. A detailed family history revealed that her great-grandfather, grandfather, father, half-brother, great-aunt, great-aunt's son and two grandsons, as well as her aunt and aunt's son, had similar clinical manifestations. WES revealed that she has harbored a heterozygous c.556-16(IVS1)C>G (NM_000424.4) variant in the KRT5 gene, which was identified as a splice site mutation. Reverse transcription sequencing confirmed that this variant can disrupt normal splicing, resulting in retention of a 15 bp sequence in the first intron. Sanger sequencing demonstrated that the variant was inherited from the father, and the 6 aforementioned relatives with similar phenotypes have all carried the same variant (the great-grandfather, grandfather, and great-aunt had declined genetic testing due to advanced age). Based on the ACMG guidelines, this variant was classified as pathogenic (PS3+PM2_Supporting+PP3+PP1_strong).
CONCLUSION:Patients with epidermolysis bullosa simplex may exhibit clinical features including blistering on the skin or mucous membranes of friction-prone sites (e.g. hands, feet, elbows, and knees) following minor trauma or friction, as well as increased skin fragility. The c.556-16(IVS1)C>G (rs376462752) variant of the KRT5 gene probably underlay the pathogenesis of EB in this child. Above findings have enriched the mutational spectrum of the KRT5 gene.
