卢旺达乳腺癌病例中发现共同的 BRCA1 致病奠基者变异
A common pathogenic founder variant in Rwandan breast cancer cases
研究在 175 名卢旺达乳腺癌女性中发现，7 名无亲缘关系的携带者（占病例 4%、占致病性变异携带者 22%）携带同一个 BRCA1 移码变异 c.4065_4068del（p.Asn1355Lysfs*10）。该变异在 gnomAD 中极为罕见，却在欧洲、亚洲和中东队列中反复出现。对 7 名携带者的全外显子组测序和单倍型分析显示，变异周围存在约 581 kb 的共享祖先区块，扩展单倍型纯合度和网络分析支持共同奠基者起源，基于溯祖的年龄估计将该奠基事件定在约 4,000–10,000 年前。
来源：PLOS Genetics · journals.plos.org
by Achille V. C. Manirakiza, Shakuntala Baichoo, Annette Uwineza, Damas Dukundane, Eulade Rugengamanzi, Janviere Mutamuliza, Allison M. O. Niragira, Raissa Muvunyi, Jeffrey Besada, Sarah M. Nielsen, Brianna Bucknor, Diane R. Koeller, Caroline Andrews, Leon Mutesa, Temidayo Fadelu, Timothy R. Rebbeck
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.