187 Genetic Diagnosis of Pachyonychia Congenita and Keratoderma

The International Pachyonychia Congenita Research Registry (IPCRR) was established by Pachyonychia Congenita Project (www.pachyonychia.org) to confirm diagnosis of pachyonychia congenita (PC) by genetic testing and to collate clinical and molecular data from PC patients worldwide. IPCRR enrollment is by patient online self-referral or via clinician referral. Clinical telephone consultations are performed by dermatologists associated with PC Project combined with free genetic testing (University of Dundee). PC is a rare autosomal dominant keratinising disorder characterised by severe plantar pain, palmoplantar keratoderma and hypertrophic nail dystrophy. The underlying genetic cause is a mutation in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. As of April 2017, IPCRR had collected clinical and molecular data from 774 PC patients (419 families). 113 distinct mutations have been identified. An equally important service through IPCRR has been the exclusion of keratin mutations from a small number of misdiagnosed patients who present with some features of PC. In 56 cases we provided a correct diagnosis by identifying mutations in genes including GJB6, TRPV3, DSG1, DSP, AAGAB or FZD6. With the development of NGS, we developed a gene panel for the 5 PC keratin genes plus DSG1, GJB6, TRPV3 and AAGAB. Mutations were identified in 46 of 51 cases recently enrolled in IPCRR; KRT6A (21), KRT6B (4), KRT16 (12), KRT17 (4), DSG1 (2), Cx30 (1), AAGAB (1), TRPV3 (1), no mutation (5). Four are previously unreported mutations. The panel is now being expanded to cover all known keratoderma genes. This will also help identify mutations in atypical cases or where Sanger sequencing failed to identify a mutation. Currently there are no effective treatments for PC and other keratoderma. The wealth of clinical and molecular data collected by IPCRR not only ensures correct diagnosis for patients but is driving development of future therapies.