Sephardic origins revealed for rare skin disorder, recessive dystrophic epidermolysis bullosa, in individuals carrying the unique c.6527insC mutation

Journal
Journal of Medical Genetics
ISSN
0022-2593
Date Issued
2025-09-24
Author(s)
Emily Mira Warshauer
Paul A Maier
Goran Runfeldt
Maria José Escamez
Laura Valinotto
Monica Natale
Graciela Manzur
Nuria Illera
Marta Garcia
Marcela Del Rio
Angeles Mencia
Almudena Holguin
Fernando Larcher
Garrett Hellenthal
Adam R Brown
Liliana Consuegra
Carolina Rivera
Inês Nogueiro
Jean Tang
Anthony Oro
Peter Marinkovich
Francis Palisson
Matthias Titeux
Alain A Hovnanian
Eli Sprecher
Karl Skorecki
David Norris
Anna Bruckner
Igor Kogut
Ganna Bilousova
Dennis Roop
Type
journal-article
DOI
URL
Abstract
Background 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 among individuals with RDEB and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation; however, individuals with RDEB are not known to have predominant Jewish ancestry. Methods In this study, a global cohort of individuals with RDEB 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. Age estimation analysis was performed to determine when Jewish founders introduced the c.6527insC mutation into Iberian and Native American populations (similar to 900 CE and 1492 CE, respectively). Results 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. Identical-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 RDEB subpopulation. Conclusion The identification of this unique RDEB subpopulation unified by the single most prevalent c.6527insC mutation holds great potential to facilitate promising new RDEB therapies using CRISPR Cas 9 gene and base editing. The identification of a single guide RNA allowing efficient and safe editing of this variant would represent a unique drug to treat a large cohort of patients with the same founder mutation.
Cite this document
Warshauer, E. M., Maier, P. A., Runfeldt, G., Fuentes, I., Escamez, M. J., Valinotto, L., Natale, M., Manzur, G., Illera, N., Garcia, M., Del Rio, M., Mencia, A., Holguin, A., Larcher, F., Hellenthal, G., Brown, A. R., Consuegra, L., Rivera, C., Nogueiro, I., … Roop, D. (2025). Sephardic origins revealed for rare skin disorder, recessive dystrophic epidermolysis bullosa, in individuals carrying the unique c.6527insC mutation. Journal of Medical Genetics, jmg-2025-110967. https://doi.org/10.1136/jmg-2025-110967