Limitaciones de los estudios de genética molecular en el proceso diagnóstico de fibrosis quística

Alicia Vaglio; Lucilla Pizzo; Andrea Quadrelli; Rosario Gueçaimburú; Sinthia Pagano; Roberto Quadrelli

Alicia Vaglio Instituto de Genética Médica (IGM). Médica Pediatra Genetista
Lucilla Pizzo Instituto de Genética Médica (IGM). Licenciada en Bioquímica
Andrea Quadrelli Instituto de Genética Médica (IGM). PhD. en Antropología. Licenciada en Biología
Rosario Gueçaimburú Instituto de Genética Médica (IGM). Médica Pediatra Genetista
Sinthia Pagano Instituto de Genética Médica (IGM). PhD. Química Farmacéutica
Roberto Quadrelli Instituto de Genética Médica (IGM). Académico. Médico Genetista

Keywords: CYSTIC FIBROSIS

Abstract

Introduction: cystic fibrosis is an autosomal recessive hereditary disease caused by mutations of the gene which encodes a protein with a CFTR chloride channel function. It appears as a multi-organ disease and is characterized by a great clinical heterogeneity. There are patients who do not evidence the classic clinical characteristics and are described as atypical or non-classic cystic fibrosis. Diagnosis is based on a consistent clinical phenotype and evidence of dysfunction in the CFTR channel and/or in the identification of two mutations causing cystic fibrosis. None of these definitions is enough in itself to confirm diagnosis.
Objectives: to show a few limitations on the molecular genetic studies in the cystic fibrosis diagnostic process.
Method: five clinical cases of children referred with clinical data of probable cystic fibrosis were considered, and they were requested a genetic study to confirm diagnosis.
Results: studies conducted do not enable the confirmation of cystic fibrosis diagnosis and neither do they allow discarding a possible diagnosis of atypical cystic fibrosis.
Conclusions: in most cases the diagnosis of cystic fibrosis is clear and genetic studies enable the confirmation of diagnosis, genetic counseling and the final prenatal diagnosis. However, use and interpretation of genetic analysis result in several difficulties regarding the clinical and paraclinical characteristics of patients, technical limitations and choosing the mutations to be analysed, especially in the case of atypical cystic fibrosis. The present study shows the challenge faced by clinicians when interpreting a molecular result to incorporate it into the cystic fibrosis diagnostic process.

References

(1) Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ; Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG. American College of Medical Genetics. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 2001; 3(2): 149-54.
(2) Welsh MJ, Ramsey BW, Accuso F, Cutting GR. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8 ed. Nueva York: McGraw-Hill, 2001: 5121-88.
(3) De Boeck, K. Procedimientos diagnósticos, características clínicas y asesoramiento en la fibrosis quística. Ann Nestlé [Esp] 2006; 64(3): 119-30.
(4) Castellani C, Cuppens H, Macek M Jr, Cassiman JJ, Kerem E, Durie P, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008; 7(3): 179-96.
(5) Segal, E. ¿Es de interés para el pediatra un consenso sobre diagnóstico y tratamiento de los pacientes con fibrosis quística? Arch Argent Pediatr 2008; 106(4): 293-4.
(6) Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and dumping. Science 1989; 245(4922): 1059-65.
(7) Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245(4922): 1066-73
(8) Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245(4922): 1073-80.
(9) Canada. Hospital for Sick Children. Cystic Fibrosis Centre. Cystic Fibrosis Mutation Database. Disponible en: http://www.genet.sickkids.on.ca/cft. Consulta: 20 noviembre 2010.
(10) Luzardo G, Aznárez I, Crispino B, Mimbaca A, Martínez L, Poggio R, et al. Cystic fibrosis in Uruguay. Genet Mol Res 2002; 1(1): 32-8.
(11) Mateu E, Calafell F, Ramos MD, Casals T, Bertranpetit J. Can a place of origin of the main cystic fibrosis mutations be identified? Am J Hum Genet 2002; 70(1): 257-64.
(12) Noone PG, Knowles MR. 'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulador gene mutations. Respir Res 2001; 2(6): 328-32.
(13) Cardoso H, Crispino B, Mimbacas A, Cardoso ME. A low prevalence of cystic fibrosis in Uruguayans of mainly European descent. Genet Mol Res 2004; 3(2): 258-63.
(14) Grimberg J, Nawoschik S, Belluscio L, McKee R, Turck A, Eisenberg A. A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acids Res 1989; 17(20): 8390.
(15) Mittre H, Duhamel JF, Abeguile G, Lemaire M, Leymarie P. A novel splice mutation, 4006-1G>A, in intron 21 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat 2000; 15(1): 121.
(16) Groman JD, Hefferon TW, Casals T, Bassas L, Estivill X, Des Georges M, et al. Variation in a repeat sequence determines whether a common variante of the cystic fibrosis transmembrane conductance regulador gene is pathogenic or beningn. Am J Hum Genet 2004; 74(1): 176-9.
(17) Claustres M, Laussel M, Desgeorges M, Giansily M, Culard JF, Razakatsara G, et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet 1993; 2(8): 1209-13.

Limitations to molecular genetics studies during the cystic fibrosis diagnostic process

Abstract

References

Follow on Twitter