Cystic Fibrosis Syndrome: A New Paradigm for Inherited Disorders and Implications for Molecular Diagnostics

Abstract

In this issue, Castaldo et al. (1) describe the use of denaturing gradient gel electrophoresis to scan the CFTR gene in cystic fibrosis (CF) patients from Southern Italy who were negative for the common CF mutations. As expected, rare mutations were found, five of which were useful in population screening. These findings are particularly important for laboratories in Italy and in areas with families of Italian descent. Advanced molecular techniques provide a double-edged sword because they often detect sequence changes whose deleterious natures are by no means established. In the CFTR gene, such variants may cause classic CF, elicit atypical phenotypes with similarities to CF, or have no consequence to health. Among recent letters in the New England Journal of Medicine on mild phenotypic variants of CF (2)(3)(4), one suggested that “the diagnosis of cystic fibrosis is too nebulous to preserve in clinical practice and that perhaps, as is the case with Cushing’s disease and syndrome, we need to have both a cystic fibrosis ‘disease’. . . and a cystic fibrosis ‘syndrome’ (which would include the pancreatic manifestations, congenital bilateral absence of the vas deferens, or lesser pulmonary manifestations)” (3). As improved mutation detection technologies enter the clinical laboratory and identify rare CFTR mutations, laboratorians and clinicians must be cognizant of the changing nature of genotype-phenotype associations. The severity of the pancreatic and hepatic features of CF is highly variable. The gastrointestinal presentations endured by CF patients take many forms (5). The majority of patients (85–90%) experience pancreatic exocrine insufficiency. Those who retain pancreatic exocrine function (10–15%) typically carry at least one of the CFTR gene mutations that have been associated with residual function. Other CF patients have impaired endocrine insulin production associated with diabetes (10–15% of patients) or liver dysfunction (5), although no specific CFTR …