Abstract
The goal of the present study was to provide a complete and updated spectrum of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutations in the Brazilian population combining all available in silico data for patients with CF in Brazil, including founder background and migration flow that consisted of the actual genetic pool of the Brazilian population. Information sources in international databases (PUBMED and SCIELO) were searched. The Brazilian population shows a wide variation in the frequency of CFTR mutations in states Rio Grande do Sul (RS), Santa Catarina (SC), Paraná (PR), São Paulo (SP), Rio de Janeiro (RJ), Minas Gerais (MG), Pará (PA) and Bahia (BA); this variation includes the most common mutation p.F508del. Apparently, this frequency variation is because of the different ethnic compositions. States such as SC and PR have a greater European admixture with almost 90% of CF alleles identified. In other states, such as BA, higher frequency of alleles that are common among African populations is seen. Overall, the CFTR mutational spectrum indicates the presence of European, African and Amerindian ethnic groups in the contemporary Brazilian CF patients. Here, we present an analysis of the CFTR allelic heterogeneity and discuss the origin of its genetic composition, in an attempt to provide improved perspective for the CF population screening in Brazil and genetic counseling.
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References
Boat, T., Welsh, M. & Beaudet, A. Cystic fibrosis In The Metabolic Basis Of Inherited Disease 6th edn (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D) 2649–2680 (McGraw-Hill: New York, 1989).
Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066–1073 (1989).
Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M. et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065 (1989).
Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).
Zielenski, J., Fujiwara, T. M., Markiewicz, D., Paradis, A. J., Anacleto, A. I., Richards, B. et al. Identification of the M1101 K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the Hutterite population. Am. J. Hum. Genet. 52, 609–615 (1993).
Cuppens, H., Marynen, P., De Boeck, C. & Cassiman, J. J. Detection of 98 5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene. Genomics 18, 693–697 (1993).
Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I. et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat. Genet. 1, 188–191 (1992).
Abeliovich, D., Lavon, I. P., Lerer, I., Cohen, T., Springer, C., Avital, A. et al. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am. J. Hum. Genet. 51, 951–956 (1992).
Casals, T., Ramos, M. D., Gimenez, J., Larriba, S., Nunes, V. & Estivill, X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum. Genet. 101, 365–370 (1997).
Claustres, M., Guittard, C., Bozon, D., Chevalier, F., Verlingue, C., Ferec, C. et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum. Mutat. 16, 143–156 (2000).
Raskin, S., Pereira, L., Reis, F., Rosario, N. A., Ludwig, N., Valentim, L. et al. High allelic heterogeneity between Afro-Brazilians and Euro-Brazilians impacts cystic fibrosis genetic testing. Genet. Test. 7, 213–218 (2003).
des Georges, M., Guittard, C., Altieri, J. P., Templin, C., Sarles, J., Sarda, P. et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J. Cyst. Fibros. 3, 265–272 (2004).
Tsui, L. C. Population analysis of the major mutation in cystic fibrosis. Hum. Genet. 85, 391–392 (1990).
Estivill, X., Bancells, C. & Ramos, C. Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations The Biomed CF Mutation Analysis Consortium. Hum. Mutat. 10, 135–154 (1997).
Morales-Machin, A., Borjas-Fajardo, L., Pineda, L., Gonzalez, S., Delgado, W., Zabala, W. et al. [Frequency of delta F508 mutation in Venezuelan patients with cystic fibrosis]. Invest. Clin. 45, 121–130 (2004).
Raskin, S., Phillips IIIrd, J. A., Krishnamani, M. R., Vnencak-Jones, C., Parker, R. A., Rozov, T. et al. DNA analysis of cystic fibrosis in Brazil by direct PCR amplification from Guthrie cards. Am. J. Med. Genet. 46, 665–669 (1993).
CFMDB. Cystic Fibrosis Mutation Database. http://www3.genet.sickkids.on.ca/cftr/ last accessed—18 June (2009).
Raskin, S., Phillips, J. A., Kaplan, G., McClure, M., Vnencak-Jones, C., Rozov, T. et al. Geographic heterogeneity of 4 common worldwide cystic fibrosis non-DF508 mutations in Brazil. Hum. Biol. 71, 111–121 (1999).
Faucz, F. R., Gimenez, J., Ramos, M. D., Pereira-Ferrari, L., Estivill, X., Raskin, S. et al. Cystic fibrosis in a southern Brazilian population: characteristics of 90% of the alleles. Clin. Genet. 72, 218–223 (2007).
Bortolini, M. C. & Salzano, F. M. Âs haplotype diversity in Afro-Americans, Africans, and Euro-Asiatics: an attempt at a synthesis. J. Braz Assoc. Adv. Sci. 51, 175–180 (1999).
Salzano, F. & Freire-Maia, N. Populaçõesbrasileiras:Aspectosdemográficos, Genéticoseantropológicos. (Companhia Editora Nacional: São Paulo, 1967).
IBGE. (Instituto Brasileiro de Geografia e Estatística) Brazilian census. Sintese de Indicadores Sociais: Uma analise das condicoes de vida da populacao brasileira (Rio de Janeiro: IBGE, 2008).
Salzano, F. & Pena, S. D. Ethics and medical genetics in Brazil In Ethics and Human Genetics: A Cross-Cultural Perspective (eds Wertz, D. & Fletcher, J.C.) 100–118 (Verlag, Heidelberg: Springer, 1987).
Monteiro, J. M. Negros da Terra, Índios e Bandeirantes Nas Origens de São Paulo. (Companhia das Letras: São Paulo, 1994).
Ribeiro, D. O. Povo Brasileiro: A Formação e o Sentido do Brasil. (Companhia das Letras: São Paulo, 1995).
Salzano, F. M. & Callegari-Jacques, S. M South American Indians. A Case Study In Evolution (Clarendon Press: Oxford, 1988).
Alves-Silva, J., da Silva Santos, M., Guimarães, P. E., Ferreira, A. C., Bandelt, H. J., Pena, S. D. et al. The ancestry of Brazilian mtDNA lineages. Am. J. Hum. Genet. 67, 444–461 (2000).
Santos, S. & Guerreiro, J. F. The indigenous contribution to the formation of the population of the Brazilian Amazon Region. Braz. J. Genet. 18, 311–315 (1995).
Dornelles, C. L., Callegari-Jackes, S. M., Robinson, W. M., Weimer, T. A., Franco, M. H. L. P., Hickmann, A. C. et al. Genetics, surnames, grandparent's nationalities and ethnic admixture in Southern Brazil: do the patterns of variation coincide? Genet. Mol. Bio. 22, 151–161 (1999).
Petzl-Erler, M. L., Luz, R. & Sotomaior, V. S. The HLA polymorphism of two distinctive South-American Indian tribes: the Kaingang and the Guarani. Tissue Antigens 41, 227–237 (1993).
Petzl-Erler, M. L. & McDevitt, H. O. Molecular analysis of the HLA-DRB genes in two tribes of Brazilian Indians. Hum. Immunol. 41, 180–184 (1994).
Salzano, F. M., Callegari-Jacques, S. M., Weimer, T. A., Franco, M. H. L. P., Hutz, M. H & Petzl-Erler, M. L. Electrophoretic protein polymorphisms in Kaingang and Guarani Indians of Southern Brazil. Am. J. Hum. Biol. 9, 505 (1997).
Faucz, F. R., Probst, C. M. & Petzl-Erler, M. L. Polymorphism of LMP2, TAP1, LMP7 and TAP2 in Brazilian Amerindians and Caucasoids: implications for the evolution of allelic and haplotypic diversity. Eur. J. Immunogenet. 27, 5–16 (2000).
Alvarez, A. E., Ribeiro, A. F., Hessel, G., Bertuzzo, C. S. & Ribeiro, J. D. Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity. J. Pediatr. 80, 371–379 (2004).
Streit, C., Burlamaque-Neto, A. C., de Abreu e Silva, F., Giugliani, R. & Saraiva Pereira, M. L. CFTR gene: molecular analysis in patients from South Brazil. Mol. Genet. Metab. 78, 259–264 (2003).
Cabello, G. M., Cabello, P. H., Otsuki, K., Gombarovits, M. E., Llerena Jr, J. C. & Fernandes, O. Molecular analysis of 23 exons of the CFTR gene in Brazilian patients leads to the finding of rare cystic fibrosis mutations. Hum. Biol. 77, 125–133 (2005).
Lopez-Camelo, J. S., Cabello, P. H. & Dutra, M. G. A simple model for the estimation of congenital malformation frequency in racially mixed populations. Braz. J. Genet. 19, 659–663 (1996).
Morral, N., Llevadot, R., Casals, T., Gasparini, P., Macek, M., Dörk, T. et al. Independent origins of cystic fibrosis mutations R334W, R347P, R1162X and 3849+10kbC → T provide evidence of mutation recurrence in the CFTR gene. Am. J. Hum. Genet. 55, 890–898 (1994).
Macek, M. J., Mackova, A., Hamosh, A., Hilman, B. C., Selden, R. F., Lucotte, G. et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am. J. Hum. Genet. 60, 1122–1127 (1997).
Friedman, K. J., Leigh, M. W., Czarnecki, P. & Feldman, G. L. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am. J. Hum. Genet. 62, 195–196 (1998).
Araujo, F. G., Novaes, F. C., Santos, N. P., Martins, V. C., Souza, S. M., Santos, S. E. et al. Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil. Braz. J. Med. Biol. Res. 38, 11–15 (2005).
Costa, F. M. M., Santana, M. A., Lemos, A. C. M., Galvão-Castro, B. & Acosta, A. G. Low frequency of the DF508 mutation of the CFTR gene in a highly admixed population in Bahia. Brazil. Hum. Biol. 79, 293–297 (2007).
Estivill, X., Farral, M., Scambler, P. J., Bell, G M, Hawley, K M, Lench, N J et al. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. Nature 326, 840–845 (1987).
Estivill, X., Scambler, P. J., Wainwright, B. J., Hawley, K., Frederick, P., Schwartz, M. et al. Patterns of polymorphisms and linkage disequilibrium for cystic fibrosis. Genomics 1, 257–263 (1987).
Cystic Fibrosis Genetic Analysis Consortium (CFGAC). Newsletter 67 (1996).
Raskin, S., Phillips, J. A. & Krishnamani, M. R. S. Regional distribution of cystic-fibrosis linked DNA haplotypes in Brazil: multicenter study. Hum. Biol. 69, 75–88 (1997).
European Working Group on CF Genetics.. Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum. Genet. 85, 436–446 (1990).
Dork, T., Neumann, T., Wulbrand, U., Wulf, B., Kälin, N., Maass, G. et al. Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families. Hum. Genet. 88, 417–425 (1992).
Novelli, G., Gasparini, P., Savola, A., Pignatti, P F., Sangiuolo, F. & Dallapiccola, B. Polymorphic DNA haplotypes and delta F508 deletion in 212 Italian CF families. Hum. Genet. 85, 420–421 (1990).
Ferrari, M., Antonelli, M., Bellini,, F., Borgo, G., Castiglione, O., Curcio, L. et al. Genetic differences in cystic fibrosis patients with and without pancreatic insufficiency: an Italian collaborative study. Hum. Genet. 84, 435–438 (1990).
Duarte, A., Barreto, C., Marques-Pinto, L., Tavares, M C., Amil, J., Pinto, M. et al. Cystic fibrosis in the Portuguese population: haplotype distribution and molecular pathology. Hum. Genet. 85, 404–405 (1990).
Cutting, G. R., Antonarakis, S. E., Buetow, K. M., Kasch, L. M., Rosenstein, B. J. & Kazazian, H. H. Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American Black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene. Am. J. Hum. Genet. 44, 307–318 (1989).
Bossi, A., Casazza, G., Padoan, R. & Milani, S. What is the incidence of cystic fibrosis in Italy? Data from the National Registry (1988–2001). Hum. Biol. 76, 455–467 (2004).
Wiedemann, B., Steinkamp, G., Sens, B. & Stern, M. The German cystic fibrosis quality assurance project: clinical features in children and adults. Eur. Respir. J. 17, 1187–1194 (2001).
Sharp, J. K. & Rock, M. J. Newborn screening for cystic fibrosis. Clin. Rev. Allerg. Immunol. 35, 107–115 (2008).
Santos, G. P., Domingos, M. T., Wittig, E. O., Riedi, C. A. & Rosário, N. A. Neonatal cystic fibrosis screening program in the state of Parana: evaluation 30 months after implementation. J. Pediatr. 81, 240–244 (2005).
Honorio, L. F. O., Ludwig Neto, N., Barbosa, E., Perin, N., Gastaldi, L. A., Ferreira, J. E. et al. Avaliação da triagem neonatal para fibrose cística no Estado de Santa Catarina. J. Bras. Pneumol. 32, 1–16 (2006).
Reis, F., Melo, S. O. & Vergara, A. A. Programa de triagem neonatal para fibrose cística de Minas Gerais (PETN-FIBROSE CÍSTICA): aspectos clínicos e laboratoriais. J. Bras. Pneumol. 32, S1 (2006).
Rodrigues, R., Gabetta, C. S., Pedro, K. P., Valdetaro, F., Fernandes, M. I., Magalhães, P. K. et al. Cystic fibrosis and neonatal screening. Cad. Saude Publica. 24, 475–484 (2008).
Raskin, S., Pereira-Ferrari, L., Reis, F. C., Abreu, F., Marostica, P., Rozov, T. et al. Incidence of cystic fibrosis in five different states of Brazil as determined by screening of p.F508del mutation at the CFTR gene in newborns and patients. J. Cyst. Fibros 7, 15–22 (2008).
Heim, R. A., Sugarman, E. A. & Allitto, B. A. Improved detection of cystic fibrosis mutations in the heterogeneous US population using an expanded, pan-ethnic mutation panel. Genet. Med. 3, 168–176 (2001).
Bobadilla, J. L., Macek Jr, M., Fine, J. P. & Farrell, P. M. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum. Mutat. 19, 575–606 (2002).
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We thank Dr Constantine A Stratakis (NICHD, NIH, Bethesda, MD, USA) for critical review of the manuscript and useful suggestions.
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Faucz, F., Souza, D., Olandoski, M. et al. CFTR allelic heterogeneity in Brazil: historical and geographical perspectives and implications for screening and counseling for cystic fibrosis in this country. J Hum Genet 55, 71–76 (2010). https://doi.org/10.1038/jhg.2009.123
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DOI: https://doi.org/10.1038/jhg.2009.123
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