Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype–phenotype correlation analysis

BACKGROUND: Porokeratosis is a rare, genetically heterogeneous group of dyskeratotic dermatoses with an incompletely understood pathogenesis. Accumulating evidence shows that pathogenic variants in mevalonate pathway-related genes play a central role in the aetiology of the disease. Previous studies have established partial genotype-phenotype correlations, although the biological mechanisms underlying these associations remain incompletely characterized. OBJECTIVES: To analyse the germline and somatic variant spectrum of porokeratosis, unravel gene subtype-specific 'second-hit' mechanisms, and establish genotype-phenotype correlations via a large cohort, providing evidence to guide clinical practice. METHODS: We sequenced peripheral blood samples from 69 patients with porokeratosis and performed whole-exome sequencing on 37 lesional epidermis samples from 29 patients, to detect somatic second-hit changes. We reviewed the germline genotypes and phenotypes of 572 patients reported in 46 studies retrieved from PubMed and ClinVar, and analysed genotype-phenotype correlations. RESULTS: In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the 'second-hit' mechanism. By integrating this information with literature data, we summarized 10 common variants and identified novel genotypephenotype correlations: 100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71% (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants; MVK, MVD and PMVK variants were detected in patients with porokeratosis ptychotropica (PP). Somatic second-hit changes were identified in 81% (n = 55/68) of patients, mostly copy-neutral loss of heterozygosity (CN-LOH) with gene subtype specificity: most MVK-related porokeratosis showed chromosome 12-wide CN-LOH, while most MVD-related porokeratosis had 16q CN-LOH. CONCLUSIONS: Our large cohort study expands the genetic variant spectrum of porokeratosis, clarifies gene subtype-specific somatic 'second-hit' mechanisms and establishes clinically relevant genotype-phenotype correlations. These findings enable porokeratosis subtyping guided by genetic testing and provide a foundation for developing molecularly integrated scoring systems to refine risk-stratified management.