A Common Pathogenic Founder Variant in Rwandan Breast Cancer Cases
Manirakiza, A. V.; Baichoo, S.; Uwineza, A.; Dukundane, D.; Rugengamanzi, E.; Mutamuliza, J.; Niragira, A.; Muvunyi, R.; Besada, J.; Nielsen, S.; Bucknor, B.; Koeller, D. R.; Andrews, C.; Mutesa, L.; Fadelu, T.; Rebbeck, T. R.
Show abstract
Germline data from African populations remain sparse, limiting characterization of population-specific BRCA1/2 pathogenic variants. In a study of 175 Rwandan women with breast cancer, 7 unrelated carriers (4% of cases; 22% of pathogenic variant carriers) harbored the same BRCA1 frameshift variant, 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.
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