Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi

Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. We undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with Congenital Melanocytic Naevi (CMN) (male 40%, multiple CMN 76%, projected adult size (PAS) >20 cm 59%). Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with neither in 25%. Two separate naevi were sequenced in 5/7 patients with BRAF mutations, confirming clonality. 5/7 BRAF-mutated patients had a dramatic multi-nodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS was the commonest mutation in all sizes of CMN, but was particularly common in PAS >60cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wildtype patients. Importantly, the incidence of congenital neurological disease, or seemingly of melanoma, was not altered by genotype. No cases of melanoma were seen in BRAF-mutant multiple CMN, however this genotype is rare. In conclusion, in this large cohort study we document the prevalence of the two major causal genotypes, clarify the relationship between genotype and size of CMN, confirm and expand knowledge of genotype-phenotype differences with nodularity, and demonstrate no difference in neurological disease in childhood between the three genotypic groups. Genotyping of CMN should however be undertaken in suspected melanoma for guidance of treatment. This article is protected by copyright. All rights reserved