Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

Carlo Castellani, MD; Barry Linnane, MB, BCh, BAO, DCH, MRCPI, MRCPCH, MD; Iwona Pranke, PhD; Federico Cresta, MD; Isabelle Sermet-Gaudelus, MD, PhD; Daniel Peckham, MD


Semin Respir Crit Care Med. 2019;40(6):701-714. 

In This Article


Most of the CF cases are identified by mutation panels including the most common mutations, the so-called first level analysis. In case of inconclusive results, extensive sequencing of the 27 CFTR exons, as well as exon–intron junctions, intronic regions where deep intronic disease-causing variants have been reported, and a part of the promoter, can detect rare single nucleotide variants, copy number variations, but also large deletions or insertions. Next generation sequencing approach increases sensitivity of pathogenic or probably pathogenic variants to 99%.[142]

For the remaining 1% of the individuals, CFTR mRNA analysis in epithelial cells sampled by nasal brushing or rectal biopsy can identify aberrant transcripts resulting from intronic splicing mutations, such as insertion of a cryptic exon or exon deletion by abnormal exon skipping, and very rare pathogenic CFTR variants, such as deep intronic mutations.[143] These approaches increase sensitivity but identify a large number of CFTR variants of unknown or unclear clinical meaning.

Trying to understand the clinical liability of CFTR variants has been in the past years a major task of molecular biologists and clinicians. The results of such commitment are reported in dedicated websites, including those of the Clinical and Functional Translation of CFTR Project (CFTR2)[118,144] and of the French database CFTR-France, and in published clinical observations or functional explorations.[145]

CFTR2 data originate from CF patient registries, and include data on genetic analysis, sweat test, and clinical descriptions. CFTR function associated with specific mutations is evaluated mainly in transfected Fischer rat thyroid cells. In the CFTR2 website ( mutations are classified as (1) CF-causing, resulting in CF when the other allele harbors another CF-causing mutation; (2) non CF-causing, non-resulting in CF when in the other allele there is a CF-causing mutation; (3) mutations of varying clinical consequence, which in trans with a CF causing mutation can either result in CF, or in a CFTR-related disorder. CFTR-related disorders are conditions with limited impairment of CFTR function that often involve isolated organs, like in congenital absence of the vas deferens or chronic pancreatitis, and are not clearly associated with severe life-shortening lung disease.[146]

Alternative ways of clustering CFTR sequence variations have been proposed by the "Screening and uncertain diagnosis of cystic fibrosis" working group of the French CF Society:[147] Group A mutations, analogous to CF-causing; Group B mutations, that result in a CFTR-related disorder and are usually associated with residual function of CFTR and mainly encountered in adult patients with single-organ impairment; Group A/B mutations, associated with a wide phenotypic spectrum, from standard CF to CFTR-related disease or even no clinical symptoms; Group C mutations, with no known pathogenic effect and observed in trans with a CF-causing mutation in asymptomatic individuals; Group D mutations, for which observational, bibliographic, and functional data do not allow any conclusion.

The great effort to organize CFTR sequence variations according to categories has been and is essential to optimize the use of genetic analysis for CF diagnosis. However, these classifications do not completely fit into the continuous spectrum of CFTR dysfunction and phenotypic consequences, the latter being influenced by modifier genetic factors and non-genetic environmental influences.[113] Clinical heterogeneity in the same genotypes is accounted for also by incomplete penetrance of some mutations. This is the case of the polymorphic string of thymidines (T), near the splice acceptor site in intron 8 of the CFTR gene (5T, 7T, 9T).[148] These alleles in conjunction with the F508del/R117H genotype may result in a CFTR-related disorder (R117H/7T), CF (R117H/5T), or no disease (R117H/9T).

The loose genotype/phenotype correlation, in particular as far as CF lung disease is concerned, supports, in selected cases, the evaluation of CFTR function as a surrogate marker for CF diagnosis. Functional CFTR assays document not only the presence of CFTR but also its ion transport activity, thus distinguishing patients with CFTR dysfunction and those whose normal CFTR function indicates they are unlikely to have CF.[149,150] CFTR activity can be indirectly assessed by measuring sweat chloride concentration or the transepithelial potential difference in nasal or intestinal epithelia.[151]