Germline and Somatic Second-Hit Changes in Porokeratosis: Comprehensive Variant Spectrum and Genotype-Phenotype Correlation Analysis

Background Porokeratosis (PK) is a rare, genetically heterogeneous group of dyskeratotic dermatoses with incompletely understood pathogenesis. Accumulating evidence demonstrates that pathogenic variants in mevalonate pathway-related genes play a central role in disease etiology. Previous studies have established partial genotype-phenotype correlations, though the biological mechanisms underlying these associations remain incompletely characterized. Objectives To analyze the germline and somatic variant spectrum of PK, unravel subtype-specific “second-hit” mechanisms, and establish genotype-phenotype correlations via a large cohort, thereby providing evidence to guide clinical practice. Methods We sequenced peripheral blood samples from 69 PK patients and performed whole exome sequencing (WES) on 37 lesional epidermis from 29 patients to detect somatic second-hit changes. We reviewed germline genotypes and phenotypes of 572 patients from 46 studies in PubMed and ClinVar, and analyzed genotype-phenotype correlations. Results In 69 Chinese PK patients, 22 pathogenic variants were detected in MVK, MVD, and FDPS, including 7 novel variants, 4 of which were validated via the “second-hit” mechanism. Integrating with literature data, we summarized 10 common variants and identified novel genotype-phenotype correlations: 100% (6/6) of PK patients with non-melanoma skin cancer (NMSC) and 70.83% (17/24) of linear porokeratosis (LP) harbored MVD variants; MVK, MVD and PMVK variants were detected in patients with porokeratosis ptychotropica (PP). Somatic second-hit changes were identified in 80.88% (55/68) of the patients, mostly copy-neutral loss of heterozygosity (CN-LOH) with subtype specificity: most MVK-related PP showed chr12-wide CN-LOH, while most MVD-related subtypes (LP, DSAP) had 16q CN-LOH. Conclusions Our large-cohort study expands the genetic variant spectrum of PK, clarifies subtype-specific somatic “second-hit” mechanisms, and establishes clinically relevant genotype-phenotype correlations. These findings enable PK subtyping guided by genetic testing and provide a foundation for developing molecularly integrated scoring systems to refine risk-stratified management.