Emily Mira Warshauer, Paul A Maier, Goran Runfeldt, Ignacia Fuentes, 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
{"title":"Sephardic origins revealed for rare skin disorder, recessive dystrophic epidermolysis bullosa, in individuals carrying the unique c.6527insC mutation.","authors":"Emily Mira Warshauer, Paul A Maier, Goran Runfeldt, Ignacia Fuentes, 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","doi":"10.1136/jmg-2025-110967","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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 (<i>COL7A1</i>). The <i>COL7A1</i> 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.</p><p><strong>Methods: </strong>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 (~900 CE and 1492 CE, respectively).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2025-110967","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
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 (~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.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.