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

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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.

Abbreviations

ACMG
American College of Medical Genetics (http://www.acmg.net//AM/)
CBAVD
Congenital Bilateral Absence Of The Vas Deferens
CF
Cystic Fibrosis
CF EQA
Cystic Fibrosis External Quality Assessment
CFGAC
Cystic Fibrosis Genetic Analysis Consortium (http://www.genet.sickkids.on.ca)
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator
DGGE
Denaturing Gradient Gel Electrophoresis
DHPLC
Denaturing High Performance Liquid Chromatography
DIOS
Distal Intestinal Obstruction Syndrome
ENaC
Epithelial Sodium Channel
HGVS
Human Genome Variation Society (http://www.hgvs.org/)
HRMCA
High-Resolution Melting Curve Analysis
HUGO
Human Genome Organization (http://www.hugo-international.org/)
IFHGS
International Federation of Human Genetics Societies (http://www.ifhgs.org/)
MI
Meconium Ileus
MLPA
Multiplex Ligation-dependent Probe Amplification
OECD
Organization for Economic Co-operation and Development (http://www.oecd.org).

Keywords

Cystic fibrosis
CFTR
Genetic analysis
Diagnosis
Genotype/phenotype correlation

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