A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis
Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype-phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype-phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype-phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway.
Approximately 29% of the patients included in this case series, because enrolled at the CF Reference Center of Lazio (Italy) Region, were preliminarily studied by several Italian Centers from the mutational point of view by means of approaches limited to panels of the most frequent CFTR mutations. This preliminary characterization was performed as follows: 59 patients from the medical genetics section of the “Dipartimento di Biomedicina e Prevenzione, Università Tor Vergata” (Rome), 48 patients from the neonatal screening center of the “Croce Rossa Italiana” (Rome), 37 patients from the neonatal screening center of the “Dipartimento di Medicina Sperimentale, Sapienza Università di Roma” (Rome), and 32 patients from the medical genetics laboratory of the “Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena” (Milan). In about half of these patients, at least one allele with no mutation was detected. After enrollment, all these patients underwent the mutational search strategy described in Materials and Methods for confirmation of the mutation(s) already found, completion of the mutational search and allele segregation in their parents and/or relatives.
This work was supported by the following grants: Regione Lazio (research projects 2002–2005), Fondazione per la Ricerca sulla Fibrosi Cistica (project 9/2004), Fondazione Telethon (project GGP06199, 2007–2010), Istituto Pasteur Fondazione Cenci Bolognetti (project 2009–2012). S M Bruno was supported by Associazione Laziale Fibrosi Cistica. G Ferraguti was partially supported by Fondazione per la Ricerca sulla Fibrosi Cistica. S Pierandrei was partially supported by Telethon Foundation and by Associazione Laziale Fibrosi Cistica.
This work is dedicated to the late Lorena Narzi, whose great contribution made this study and other CF studies possible.
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