Large-Scale Cohort Study on the Genetic and Phenotypic Findings of Palmoplantar Keratodermas in the Chinese...

Palmoplantar keratoderma (PPK) is a heterogeneous group of skin diseases, characterised by excessive keratinization and hyperplasia of the palms and soles. However, accurate molecular diagnosis remains challenging due to the low prevalence of hereditary forms. This study analysed the phenotype and genotype distribution in a large cohort of Chinese patients with PPK, aiming to clarify the genetic aetiology and genotype-phenotype correlations. We further validated the pathogenicity of biallelic SERPINA12 variants identified in four patients. A total of 424 patients with PPK were enrolled from 2010 to 2023. Of these, 97.6% (414/424) presented with diffuse PPK, predominantly Nagashima-type PPK (NPPK), with rare cases of Olmsted, Meleda and Bothnia types. Focal PPK accounted for 1.4%, with less than 1% for striate and punctate types, respectively. Genetic testing was performed in 380 patients. Overall, 328 patients harboured pathogenic or likely pathogenic (P/LP) variants to achieve definite molecular diagnosis; none carried only variants of uncertain significance (VUS) and the remaining 52 patients had no candidate disease-associated variants identified. All patients underwent testing with an in-house customised SERPINB7 gene hotspot panel test for c.796C>T, c.522_523insT, c.806_818delinsT and c.650_653delCTGT variants. In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent. Patients not diagnosed with a hotspot variant further underwent whole-exome sequencing (WES), which identified confirmed pathogenic (P) or likely pathogenic (LP) variants in TRPV3 (c.1246C>T, c.1703G>A, c.1247G>A), AQP5 (c.530 T>A, c.367A>T), SLURP1 (c.154A>G), KRT9 (c.1373 T>C), KRT6A (c.947G>C) and KRT16 (c.379C>T). In addition, three recurrent SERPINA12 variants were identified, enriching the gene spectrum of diffuse PPK. This study established the largest cohort of patients with SERPINB7 variants reported to date, identifying that NPPK is the predominant subtype among Chinese populations. Variants in SERPINA12 are likely correlated with diffuse palmoplantar keratoderma, consistent with the clinical manifestations of NPPK. Additionally, a diagnostic panel targeting ancestral SERPINB7 founder variants would markedly improve the molecular diagnostic yield in Chinese patients.