Identification of clinically useful predictive genetic variants in pachyonychia congenita.

Background Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16, KRT6A, KRT17, KRT6B, or KRT6C). Current disease classification is based on the gene harboring disease-causing variants. Objectives We harnessed the International PC Research Registry (IPCRR) containing both clinical and molecular data on PC patients worldwide, to identify genetic variants predicting disease severity. Methods We ascertained 815 individuals harboring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analyzed using Chi-Square and Kruskal-Wallis tests. Results The KRT16 p.L132P mutation was significantly associated with younger age of onset, palmar keratoderma, oral leukokeratosis and a higher number of involved nails. In contrast, KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20 nail dystrophy. Opposite findings were observed with KRT17 p.N92S mutation. Conclusions Here we identified novel and clinically useful genetic predictive variants in the largest cohort of PC patients described to date.