ECFS standards of care on CFTR-related disorders: Diagnostic criteria of CFTR dysfunction

• DOI: 10.1016/j.jcf.2022.09.005
• Publication Date: 2022-10-05T05:15:36Z
• Authors: I. Sermet-Gaudelus; E. Girodon; F. Vermeulen; G.M. Solomon; P. Melotti; S.Y. Graeber; I. Bronsveld; S.M. Rowe; M. Wilschanski; B. Tümmler; G.R. Cutting; T. Gonska
• Keywords: Pulmonary and Respiratory Medicine; 0303 health sciences; Ion Transport; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Standard of Care; 3. Good health; 03 medical and health sciences; Mutation; Journal Article; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Humans; Sweat/metabolism; Pediatrics, Perinatology, and Child Health; Cystic Fibrosis/diagnosis; Sweat

The spectrum of disorders involving CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction correlates with a continuous gradient of CFTR function defined by the combination of two allelic CFTR variants. CFTR-related disorders are clinical entities with features of cystic fibrosis (CF) and evidence for presence of CFTR dysfunction but not meeting criteria for diagnosis of CF. Individuals with CFTR-RDs demonstrate a wide range of CFTR activity and are still under-recognized or misclassified. The level of CFTR dysfunction may be measured in vivo (sweat testing, nasal potential difference measurements) and/or by ex vivo tests (intestinal current measurement), or indirectly indicated by CFTR variants, as alteration in sequence of the CFTR gene translates into CFTR dysfunction. CFTR bioassays can aid in the diagnosis of individuals with CF, but we lack parameters to differentiate CF from CFTR-RD. In the era of the CFTR modulators and their potential clinical benefit, it is of utmost importance to diagnose CFTR-RD as unambiguously as possible. We therefore propose the following to define compatible CFTR dysfunction in a person with a suspected diagnosis of CFTR-RD : (1) evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (2) One CFTR variant known to reduce CFTR function and evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (3) Two CFTR variants shown to reduce CFTR function, with at most one CF-causing variant.