Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice

Abstract

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

Cystic fibrosis carrier screening in a North American population

“…Strom et al 7 advocate against adding these variants to CF panels, stating that detection of D1152H and L206W during carrier screening may increase the rate of pregnancy termination among parents who fear having a child with classic CF, not to mention inflating the mutation detection rate among Hispanic Americans. 7 It is acknowledged now in the literature that the D1152H variant belongs to both the CF-causing and CFTR-related disorder groups, [19][20][21] and, in conjunction with an established CF-causing mutation, it could still manifest as typical CF. 19,22 Burgel et al 23 studied 42 patients with D1152H mutations and reported that the variant, in conjunction with a CF-causing mutation, can cause significant pulmonary disease, albeit with longer survival.…”

“…7 It is acknowledged now in the literature that the D1152H variant belongs to both the CF-causing and CFTR-related disorder groups, [19][20][21] and, in conjunction with an established CF-causing mutation, it could still manifest as typical CF. 19,22 Burgel et al 23 studied 42 patients with D1152H mutations and reported that the variant, in conjunction with a CF-causing mutation, can cause significant pulmonary disease, albeit with longer survival. One of the authors of this article observed similar results (K.J.F., unpublished data).…”

Improvement of interpretation in cystic fibrosis clinical laboratory reports: longitudinal analysis of external quality assessment data

“…Their decisions are based on expert consensus and best practice guidelines, and depend on the clinical indication in the case. [13][14][15][16] Two assessors independently evaluate genotypes and interpretation in the submitted reports. Results are also discussed during an assessment meeting.…”

“…Interpretation could additionally be influenced by external factors such as the availability of best practice guidelines and publications. [13][14][15] Second, the presence in clinical reports of all investigated interpretation elements improved over the years. Two elements increased remarkably more (430%) than others: stating the need to test the parents of a CF patient to confirm homozygosity or compound heterozygosity (need for qualification of the genotype) and Interpretation in CF laboratory reports S Berwouts et al mentioning the possibility of testing the relatives.…”

Cystic Fibrosis Newborn Screening: Distribution of Blood Immunoreactive Trypsinogen Concentrations in Hypertrypsinemic Neonates

“…Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR/ABCC7; MIM #602421) induce a wide spectrum of clinical phenotypes from classic CF characterized by pancreatic insufficiency and positive sweat chloride values, to milder forms of the disease with pancreatic sufficiency, to CFTR related disorders (CFTR-RDs), where a diagnosis of CF cannot be established because the individual does not meet standard diagnostic criteria (Farrell et al 2008;Castellani et al 2008). …”