857 Crypto-Jewish origins revealed in recessive dystrophic epidermolysis bullosa individuals carrying the prevalent c.6527insC mutation associated with sephardic ancestry

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare and severe blistering skin disorder caused by loss-of-function mutations in the type VII collagen gene (COL7A1). The COL7A1 c.6527insC mutation is curiously prevalent amongst RDEB individuals and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation, however RDEB individuals are not known to have predominant Jewish ancestry. In this study, a substantial global cohort of 124 RDEB individuals with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia, and the USA were investigated by autosomal genotyping, pairwise identical-by-descent matching and a local ancestry analysis. Sephardic ancestry was identified at the haplotype spanning the c.6527insC mutation in 85% of the individuals, despite mixed ancestry elsewhere in the genome and no known recent Sephardic ancestry. Age estimation analysis was performed to determine when Jewish founders introduced the c.6527insC mutation into Iberian and Native American populations (∼900 CE and 1492 CE, respectively). Identity-by-descent matching between this RDEB subpopulation and a known crypto-Jewish community in Belmonte, Portugal was also ascertained, providing support for crypto-Jewish ancestry in this notable RDEB subpopulation. The identification of RDEB subpopulations with common origins holds great potential to enhance the efficient implementation of promising new RDEB therapies.