Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country

• Published in: Journal of cystic fibrosis Vol. 20; no. 3; pp. 473 - 484
• Main Authors: da Silva Filho, Luiz Vicente Ribeiro Ferreira, Maróstica, Paulo José Cauduro, Athanazio, Rodrigo Abensur, Reis, Francisco José Caldeira, Damaceno, Neiva, Paes, Angela Tavares, Hira, Adilson Yuuji, Schlesinger, David, Kok, Fernando, Amaral, Margarida D., Antunes, Mara Lícia Machado, Andries, Lilian Cristina Ferreira, de Castro, Virginia Auxiliadora Freitas, Adde, Fabíola Villac, Perez, Maria Fernanda Botelho Hernandez, Dantas, Vera Maria, Monte, Luciana de Freitas Velloso, Goya, Adriana, Rached, Samia, Costa, Lusmaia Damaceno Camargo, Prado, Lorenna Junqueira Almeida, Guimarães, Elizabet Vilar, de Carvalho Fernandez Fonseca, Ana Cristina, Nishi, Marina Pires, Riedi, Carlos Antônio, Filho, Nelson Augusto Rosario, Canan, Mariane Gonçalves Martynychen, Fernandes, Maria Inez Machado, Augustin, Albin Eugenio, Garcia, Rosângela Villela, da Silva Zembrzuski, Maria Margarete, de Oliveira, Kátia Izabel, Hoffmann, Anneliese, Ricachinevsky, Cláudio, de Tarso Roth Dalcin, Paulo, Ziegler, Bruna, de Souza Paiva Borgli, Daniela, Ferrao, Daniele Menezes Torres, da Silva, Elizabeth Passos Simoes, Santana, Maria Angelica, de Sousa, Maria Amenaide Carvalho Alves, de Castro e Silva, Claudia, Filho, Evalto Monte de Araujo, Veras, Tiago Neves, Neto, Noberto Ludwig, Cutolo, Luiz Roberto Agea, Vergara, Alberto Andrade, Melo, Suzana Fonseca Oliveira, Moreira, Maria do Espírito Santo Almeida, Melotti, Roberta de Cássia Nunes Cruz, Malini, Fernanda Barbosa dos Santos, de Fuccio, Marcelo Bicalho, Pessoa, Bruno Porto, Esposito, Concetta, Kussek, Paulo Cesar, Foletto, Glaunir Maria, Pinto, Leonardo Araujo, Epifanio, Matias, Rodrigues, Marcelo Tadday, Duarte, Marta Cristina, Meneses, Daniela Gois, de Carvalho Martins, Valéria, Valente, Sônia Elenita Lopes, de Azevedo Ferreira, Arlan, Cartaxo, Constantino Giovanni Braga, Haidar, Denise Maria Costa, Firmida, Mônica de Cássia, de Castro, Marcos César Santos, de Souza, Edna Lucia Santos, Mota, Lais Ribeiro, de Negreiros Moura, Katharina Vidal, Rodrigues, Joaquim Carlos, Nakaie, Cleyde Myriam Aversa, Folescu, Tânia Wrobel, Sad, Izabela, de Britto, Murilo Carlos Amorim, Castelletti, Carlos Henrique Medeiros, Gonçalves, Cláudia Mello, Muramatu, Lucia, Fischer, Gilberto Bueno, Ferrari, Giesela Fleischer, Tostes, Luciana Oliveira Silvano, Bertuzzo, Carmen Silvia, Marson, Fernando Augusto de Lima, Chiba, Sonia Mayumi, De Sillos, Marcela Duarte
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021
• Subjects: Brazil; Brazil - epidemiology; Child; Child, Preschool; Cystic Fibrosis - epidemiology; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Diagnosis; Female; Genetic Variation; Genetics; Genotype; Humans; Infant; Male; Newborn screening; Registries; Sweat chloride; Brazil; Sweat chloride; Brazil; Newborn screening; Genetics; Diagnosis
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2020.08.007

•The Brazilian population has a high degree of ethnic admixture and heterogeneity.•The CFTR variant distribution found was unexpected vs that in other populations.•Extensive negative CFTR genotyping results are likely due to CF misdiagnosis.•Regions with higher negative CFTR genotyping results have lower CF-NBS coverage.•This study identifies Brazilian Regions requiring more CF centers/ better CF care. 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. 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. 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. 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.