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. 2021 May;20(3):473-484.
doi: 10.1016/j.jcf.2020.08.007. Epub 2020 Aug 18.

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

Luiz Vicente Ribeiro Ferreira da Silva Filho  1 , Paulo José Cauduro Maróstica  2 , Rodrigo Abensur Athanazio  3 , Francisco José Caldeira Reis  4 , Neiva Damaceno  5 , Angela Tavares Paes  6 , Adilson Yuuji Hira  7 , David Schlesinger  8 , Fernando Kok  8 , Margarida D Amaral  9 ; Brazilian Cystic Fibrosis Patient Registry Contributors Team
Collaborators, Affiliations
Free article

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

Luiz Vicente Ribeiro Ferreira da Silva Filho et al. J Cyst Fibros. 2021 May.
Free article

Abstract

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.

Keywords: Brazil; Diagnosis; Genetics; Newborn screening; Sweat chloride.

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Conflict of interest statement

Declaration of Competing Interests Dr. Silva Filho reports grants and personal fees from Vertex Pharmaceuticals, grants from TimPel and Diagnostics of Americas (DASA), personal fees from Roche do Brasil, Boehringer Ingelheim, Glenmark do Brasil, AbbVie, and Sanofi, outside the submitted work. Dr. Marostica reports personal fees from Vertex Pharmaceuticals, grants from Roche, outside the submitted work. Dr. Athanazio reports grants and personal fees from Vertex Pharmaceuticals and Roche do Brasil, grant from GSK, personal fees from Pfizer, Astrazeneca, Chiesi, Novartis, and Boehringer Ingelheim, outside the submitted work. Dr. Reis has no conflicts of interest to declare. Dr. Damaceno reports personal fees from Vertex Pharmaceuticals and Roche do Brasil, outside the submitted work. Dr. Paes and Dr. Hira report personal fees from The Brazilian CF Study Group, during the conduct of the study. Dr. Schlesinger and Dr. Kok report grants from Vertex Pharmaceuticals, during the conduct of the study. Dr. Amaral reports grants and personal fees from Vertex Pharmaceuticals, PTC Pharmaceuticals, and Gilead Sciences Inc., grants from Gilead Génese Programme, Proteostasis Therapeutics, outside the submitted work. Work in MDA lab is supported by UIDB/04046/2020 and UIDP/04046/2020 centre grants (to BioISI) and research grants (to MDA): "iDrugCF" (FCT/02/SAICT/2017/28800) from from FCT/MCTES Portugal; "HIT-CF" (H2020-SC1-2017-755021) from EU; SRC 013 from CF Trust-UK; and "PTSense" (AMARAL19G0) from CFF-USA.

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