BACKGROUND The Brazilian population has a tri-hybrid composition with a high degree of ethnic admixture. We hypothesized that Brazilian individuals with CF from different Brazilian regions have a specific distribution of CFTR variants. METHODS Individuals with CF with data available in the Patient Registry and without an established genotype were submitted to CFTR sequencing by Next Generation Sequencing (NGS) methodology, and results were anonymously incorporated to the Registry Database. Genotyping results were expressed as 'positive', 'inconclusive' or 'negative'. Logistic regression models were performed to investigate the association between demographic/clinical variables and genotyping results. Mediation analysis was conducted to estimate direct and indirect effects of Brazilian region on a binary positive genotyping response. RESULTS In October 2017, data from 4,654 individuals with CF were available, and 3,104(66.7%) of them had a genotyping result. A total of 236 variants (114 new variants) were identified, with F508del identified in 46% of the alleles tested. Genotyping revealed 2,002(64.5%) individuals positive, 757(24.4%) inconclusive and 345(11.1%) negative. Distribution of genotype categories was markedly different across Brazilian Regions, with greater proportions of negative individuals in the North (45%) and Northeast (26%) regions. Newborn screening (CF-NBS) and age at diagnosis were identified as mediators of the effect of Brazilian region on a positive genotyping result. CONCLUSIONS This large initiative of CFTR genotyping showed significant regional discrepancies in Brazil, probably related to socio-economic conditions, lack of adequate CF-NBS and poor access to reliable sweat testing. These results may be useful to indicate Regions where CF care demands more attention.

中文翻译：

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通过 NGS 对巴西囊性纤维化患者进行广泛的 CFTR 测序：揭示该国的区域差异

背景技术巴西人口具有高度种族混合的三混组成。我们假设来自不同巴西地区的患有 CF 的巴西个体具有特定分布的 CFTR 变体。方法 通过下一代测序 (NGS) 方法将数据在患者登记处可用且没有确定基因型的 CF 个体提交给 CFTR 测序，并将结果匿名合并到登记处数据库中。基因分型结果表示为“阳性”、“不确定”或“阴性”。进行逻辑回归模型以研究人口统计学/临床变量与基因分型结果之间的关联。进行中介分析以估计巴西地区对二元阳性基因分型反应的直接和间接影响。结果 2017 年 10 月，共有 4,654 名 CF 患者的数据可用，其中 3,104 人（66.7%）有基因分型结果。共鉴定出 236 个变体（114 个新变体），在 46% 的测试等位基因中鉴定出 F508del。基因分型显示 2,002 (64.5%) 人为阳性，757 (24.4%) 人不确定，345 (11.1%) 人为阴性。巴西各地区的基因型类别分布明显不同，北部（45%）和东北部（26%）地区的阴性个体比例更高。新生儿筛查 (CF-NBS) 和诊断年龄被确定为巴西地区对阳性基因分型结果影响的中介因素。结论 这项大型 CFTR 基因分型计划显示巴西存在显着的区域差异，这可能与社会经济条件、缺乏足够的 CF-NBS 以及难以获得可靠的汗液测试有关。这些结果可能有助于指出 CF 护理需要更多关注的区域。