Large scale clinical exome sequencing uncovers the scope and severity of skin disorders associated with MC1R genetic variants.

Purpose Genetic variation in MC1R is a main determinant of red hair color (RHC) phenotype and confers susceptibility to skin disorders. Methods We assessed the effects and function of MC1R variants identified in our clinical cohort of 135,947 participants with available exome sequencing using phenome-wide association scan (PheWAS). Expression and function of several variants were evaluated. Results We found 24 nonsense and 215 missense variants in MC1R. Many common missense MC1R variants are strongly associated with skin disorders including skin cancer; however, each variant shows different penetrance and expressivity. Severity of skin phenotype was well correlated with the magnitude of functional defect measured as receptor expression and α-MSH stimulated cAMP production. Remarkably, MC1R deletions and nonsense variants are only weakly associated with milder skin phenotypes. Conclusion Our comprehensive assessment of all MC1R variants in a large cohort clearly establish that individuals with some missense variants are more susceptible to severe skin disorders than those with MC1R deletions or nonsense variants.