Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations

Abstract

The increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

Figure 1

Diagnostic testing in typical CF presentation. The diagnostic algorithm applies irrespective of the age of the CF patient, from newborn screening to late diagnosis in adults. While the diagnosis of CF can be based on the presence of one or more characteristic phenotypic features, a classical or typical clinical CF presentation mainly associates respiratory symptoms with pulmonary obstruction and infections, exocrine pancreatic dysfunction, and infertility in adult males, along with sweat chloride concentrations above 60 mEq/l that provide an evidence of a CFTR defect. IRT, immunoreactive trypsinaemia; NPD, nasal potential difference; ICM, intestinal chloride measurement.

Figure 2

Diagnostic testing in atypical clinical presentation and/or borderline or negative sweat test. Genetic testing is requested to confirm the diagnosis. Patients most often have residual pancreatic function (pancreatic sufficiency) but may present with acute or chronic pancreatitis. Highly variable respiratory symptoms include asthma, nasal polyposis, chronic rhinosinusitis, or disseminated bronchiectasis. CFTR-RD, CFTR-related disorder(s); CF?, mutation of uncertain clinical relevance; NPD, nasal potential difference; ICM, intestinal chloride measurement.

Figure 3

Diagnostic testing in male infertility with CBAVD. See text for diagnosis criteria for CFTR-related CBAVD. CFTR-RD, CFTR-related disorder(s).

Figure 4

Diagnostic testing in fetal bowel hyperechogenicity or loop dilatation. CF?: mutation of uncertain clinical relevance. ^aIf the gestation term is below 18 weeks and amniocentesis is performed, evaluation of fetal intestinal enzyme activities in the amniotic fluid may be considered, a dramatic decrease of all activities being suggestive of intestinal obstruction.

Figure 5

Cascade CF carrier testing. The purpose of carrier testing is to provide individuals with reproductive options and allow informed choices. Carrier testing in children should be deferred until the child can understand the issue and request the test in person. ^aReporting a negative result for familial mutation testing should be carried out cautiously if the mutation has been identified in another laboratory, unless a copy of the original report is available to the laboratory in charge of the test. ^bTest for the familial mutation may be performed in the same step as for the frequent mutations. ^cIn case the familial mutation is known and both couple members are tested in the same time, if the relative unexpectedly tests ‘negative' and the partner tests ‘positive', especially for the familial CF mutation, it is recommended to confirm the results, possibly with new samples and/or using microsatellite assays.