BRCA1 c.68_69del as a founder variant in the Spanish Roma: prevalence and screening implications

We hypothesized that the BRCA1 c.68_69del variant is highly prevalent among individuals with Roma ancestry from Spain due to a founder effect, as in the Ashkenazi Jewish population, where targeted screening has proven to be cost-effective. We conducted two cross-sectional prevalence studies in self-reported Roma adults from a community-based and a nationwide sample. To assess variant origin, we reconstructed haplotypes in carriers with Roma, Indian, Ashkenazi Jewish and European ancestry, and compared haplotype sharing and mutation-age estimates. BRCA1 c.68_69del variant was detected in 3.6% (16/440) of the community-based Roma sample and 0.8% (2/258) of the nationwide Roma sample. Roma carriers shared extended haplotypes (1.4-16.9 Mb) with carriers of presumed European and Ashkenazi Jewish ancestry, supporting a common founder, whereas minimal overlap (65 kb) with the Indian-ancestry carrier suggested an independent origin, despite the Roma population's Indian origin. Mutation-age estimates were 925 years ago in non-Roma carriers and 600 years ago in Roma carriers. Shared haplotypes support an Iberian founder later enriched in Roma, likely leading to a high prevalence of BRCA1 c.68_69del in Spanish Roma and supporting targeted genetic screening within this community.