A common pathogenic founder variant in Rwandan breast cancer cases

@article{manirakiza2026common,
  title = {{A common pathogenic founder variant in Rwandan breast cancer cases}},
  author = {Achille V. C. Manirakiza and Shakuntala Baichoo and Annette Uwineza and Damas Dukundane and Eulade Rugengamanzi and Janviere Mutamuliza and Allison M. O. Niragira and Raissa Muvunyi and Jeffrey Besada and Sarah M. Nielsen and Brianna Bucknor and Diane R. Koeller and Caroline Andrews and Leon Mutesa and Temidayo Fadelu and Timothy R. Rebbeck},
  journal = {PLOS Genetics},
  year = {2026},
  month = nov,
  doi = {10.1371/journal.pgen.1012180},
  url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012180},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - A common pathogenic founder variant in Rwandan breast cancer cases
AU  - Achille V. C. Manirakiza
AU  - Shakuntala Baichoo
AU  - Annette Uwineza
AU  - Damas Dukundane
AU  - Eulade Rugengamanzi
AU  - Janviere Mutamuliza
AU  - Allison M. O. Niragira
AU  - Raissa Muvunyi
AU  - Jeffrey Besada
AU  - Sarah M. Nielsen
AU  - Brianna Bucknor
AU  - Diane R. Koeller
AU  - Caroline Andrews
AU  - Leon Mutesa
AU  - Temidayo Fadelu
AU  - Timothy R. Rebbeck
PY  - 2026
DA  - 2026/11/02
JO  - PLOS Genetics
DO  - 10.1371/journal.pgen.1012180
UR  - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012180
AB  - Germline data from African populations remain sparse, limiting characterization of population-specific BRCA1/2 pathogenic variants (PV). In a study of 175 Rwandan women with breast cancer, 7 unrelated carriers (4% of cases; 22% of PV carriers) harbored the same BRCA1 frameshift PVs, c.4065_4068del (p.Asn1355Lysfs*10), which is extremely rare in gnomAD yet recurrent in European, Asian, and Middle Eastern cohorts. Whole-exome sequencing and haplotype analysis of all 7 carriers revealed a shared ancestral block of approximately 581 kb surrounding the variant, and extended haplotype homozygosity and network analyses confirmed a common founder origin. Coalescent-based age estimation placed the founder event approximately 4,000--10,000 years ago. Comparison with 1000 Genomes Project data showed the founder haplotype is absent or exceedingly rare outside African and South Asian populations. These findings strongly suggest the c.4065_4068del variant as a pre-historical BRCA1 founder variant in Rwanda, with implications for targeted genetic testing, cascade screening, and cancer prevention in the region. Author summary: Breast cancer is rising rapidly across sub-Saharan Africa, yet little is known about inherited gene variants that drive hereditary risk in African women. We investigated a recurring mutation in the BRCA1 gene, whose normal function protects against breast and ovarian cancer. We observed this mutation at unexpectedly high frequency among Rwandan women with breast cancer. We found that 7 of 175 women tested (4%) carried the exact same BRCA1 mutation, called c.4065_4068del, despite none being known relatives. To determine whether this recurrence reflected a shared ancestor, we analyzed the DNA surrounding the mutation in all 7 women. All 7 carried a nearly identical DNA stretch around the mutation, a hallmark of what geneticists call a “founder effect,” where a mutation present in one common ancestor spreads to many descendants over generations. Formal relatedness testing confirmed the women are not closely related, meaning this shared mutation traces back thousands of years to a common prehistoric ancestor. All 7 carriers had triple-negative breast cancer, one of the most aggressive subtypes, and most presented with advanced disease. These findings have direct implications for genetic counseling, population-level testing, and cancer prevention in Rwanda and neighboring East African countries.
SN  - 1553-7404
ER  -