Severe phenotype in an apparent homozygosity caused by a large deletion in the CFTR gene: a case report

da Silva Martins et al. BMC Research Notes 2014, 7:583 http://www.biomedcentral.com/1756-0500/7/583 CASE REPORT Open Access Severe phenotype in an apparent homozygosity caused by a large deletion in the CFTR gene: a case report Raisa da Silva Martins1, Ana Carolina Proença Fonseca1, Franklyn Enrique Samudio Acosta2,3, Tania Wrobel Folescu4, Laurinda Yoko Shinzato Higa4, Izabela Rocha Sad4, Célia Regina Moutinho de Miranda Chaves5, Pedro Hernan Cabello1,6 and Giselda Maria Kalil Cabello1* Abstract Background: Over 1900 mutations have been identified in the cystic fibrosis conductance transmembrane regulator gene, including single nucleotide substitutions, insertions, and deletions. Unidentified mutations may still lie in introns or in regulatory regions, which are not routinely investigated, or in large genomic deletions, which are not revealed by conventional molecular analysis. The apparent homozygosity for a rare, cystic fibrosis conductance transmembrane regulator mutation screened by standard molecular analysis should be further investigated to confirm if the mutation is in fact homozygous. We describe a patient presenting with an apparent homozygous S4X mutation. Case presentation: A 13-year-old female patient of African descent with clinical symptoms of classic cystic fibrosis and a positive sweat test (97 mEq/L, diagnosed at age 3 years) presented with pancreatic insufficiency and severe pulmonary symptoms (initial lung colonization with Pseudomonas aeruginosa at age 4 years; forced vital capacity: 69%; forced expiratory volume: 51%; 2011). Furthermore, she developed severe acute lung disease and recurrent episodes of dehydration requiring hospitalization. The girl carried the CFTR mutation S4X in apparent homozygosity. However, further analysis revealed a large deletion in the second allele that included the region of the mutation. The deletion that we describe includes nucleotides 120–142, which correspond to a loss of 23 nucleotides that abolishes the normal translation initiation codon. Conclusion: This study reiterates the view that large, cystic fibrosis conductance transmembrane regulator deletions are an important cause of severe cystic fibrosis and emphasizes the importance of including large deletions/duplications in cystic fibrosis conductance transmembrane regulator diagnostic tests. Keywords: Cystic fibrosis, CFTR, Apparent homozygosis, Large deletion, Severe phenotype, Brazilian patient Background Cystic fibrosis (CF; Omin #219700), the most frequent, lifelimiting autosomal recessive disorder among Caucasians, is caused by mutations in the cystic fibrosis conductance transmembrane regulator (CFTR) gene [1]. In Europe, the carrier frequency is 1:25, resulting in a disease incidence of 1 in 2500 live births [2]. However, this incidence is quite variable, with a range from 1/500 in Ohio Amish to 1/ * Correspondence: 1 Laboratório de Genética Humana, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Pavilhão Leônidas Deane sala 611. CEP: 21040-360 Avenida Brasil 4365, Rio de Janeiro, Brazil Full list of author information is available at the end of the article 90000 in Hawaiian Orientals [3]. The CFTR gene is characterized by an extremely large number of mutations (more than 1900) [4], the most common being the F508del. Other disease-causing mutations are distributed throughout all regions of the world, often with very low frequencies, making the molecular diagnosis difficult, especially in countries outside the European axis where the F508del frequency is relatively low, as observed in countries where ethnic composition is not predominantly Caucasian. Brazil is a typical example where the molecular diagnosis of CF is difficult owing to its multi-ethnic characteristics with a significant African component. © 2014 da Silva Martins et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. da Silva Martins et al. BMC Research Notes 2014, 7:583 http://www.biomedcentral.com/1756-0500/7/583 Page 2 of 4 The design of diagnostic tests available on the market is usually based on the mutation panel of European or North American populations, which is unsuitable for Brazil. Little is known about the incidence of CF in Brazil, but it does vary among different regions of the country [5-8]. Among the European countries that contributed to the current ethnic composition of our population, the F508del allele frequency is 71.8% in Germany, 51% in Italy, 53% in Spain, 57% in Poland, 58% in Slovenia, and 45% in Portugal; the latter is the main Brazilian Caucasian component [9,10]. The migratory waves from different regions of Europe, the intense inter-ethnic gene flow and different proportions of mixing genes of Caucasian, African, and Amerindian origins may explain the variation in the prevalence of the F508del mutation among different Brazilian regions [11]. Over the past 10 years, the F508del mutation contributed 30% of CF alleles in the State of Rio de Janeiro and disease incidence was estimated at 1/6902 live births [12]. Given the current annual number of births of 220,603 (Records of the Ministry of Health of Brazil, 2011; http://www2.datasus.gov.br/DATASUS/index.php), approximately 32 patients are born with CF each year. Until now, mutation screening allowed us to identify 29 different mutant alleles in CF patients from Rio de Janeiro. However, the detection rate is only 60%, which means that 40% of alleles remain unknown. Over 1900 mutations have been identified throughout the CFTR gene, including single nucleotide substitutions, insertions, and deletions. Unidentified mutations may still lie in introns or in regulatory regions, which are not routinely investigated, or in large genomic deletions, which are not revealed by conventional molecular analysis. The apparent homozygosity for a rare CFTR mutation screened by standard molecular analysis should be further investigated to confirm if the mutation is in fact homozygous. Apparent homozygosity can result from a mutation of one allele and the presence of a large deletion encompassing the location of the first mutation on the second allele [13]. We describe a patient carrying the S4X mutation (CM930095) in apparent homozygosity; further analysis revealed that it was heterozygous with a large deletion that includes nucleotides 120–142, which corresponds to a loss of 23 nucleotides coding the first exon of the CFTR gene. This deletion removes a region from position -12 to position 10, including codons 1, 2, 3, and 4 of exon 1. Results The suspected presence of a large deletion (...truncated)