וריאנטים גנטים הקשורים בפכיוניכיה קונגניטה והמנבאים חומרת מחלה

Background: Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in one of 5 keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). Current disease classification is based on the mutant gene and associated features. Here we harness the International PC Research Registry (IPCRR) resource containing both clinical and molecular data on PC patients worldwide, to identify genetic variants predicting disease severity.

Patients and methods: 815 individuals with confirmed keratin mutations registered in the IPCRR. Only mutations identified in at least 10% of patients carrying mutations in each of the 5 PC-associated genes were chosen and surveyed for clinical features. These were compared to clinical manifestations associated with other mutations in the same gene. Data were analyzed using Chi-Square and Kruskal-Wallis tests.

Results: The KRT16 p.L132P mutation was significantly associated with increased number of involved nails, palmar keratoderma and oral leukokeratosis with a younger age of onset. 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 nails dystrophy. Opposite findings were observed with KRT17 p.N92S mutation.

Conclusions: Here we reveal novel and clinically useful genetic predictive variants in the largest cohort of PC patients described to date.