Abstract
BackgroundCFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented.MethodsBelgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF+RM). Clinical data and sweat chloride of CF+RM were compared to CF-controls, carrying 2 class 1 to 3 mutations (CFclassic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group.ResultsSeventy-seven CF+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data.Seven transplanted CF+RM were excluded for further analysis. CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3–18.3) vs. 0.3y (0.1–2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64–107) vs. 104 mmol/L (97–115) (p < 0.0001)], higher FEV1%pred [77%pred (58–96) vs. 68%pred (48–86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic. However, a wide spectrum of disease severity was seen amongst CF+RM.ConclusionsCF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients.
Highlights
CFTR2 provides clinical and functional information of the most common Cystic Fibrosis Transmembrane Regulator (CFTR)-mutations
Seven transplanted Cystic fibrosis (CF) with at least rare CFTR mutation’ (RM) (CF+RM) were excluded for further analysis
CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3–18.3) vs. 0.3y (0.1–2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64–107) vs. 104 mmol/L (97–115) (p < 0.0001)], higher FEV1%pred [77%pred (58–96) vs. 68%pred (48–86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic
Summary
CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented. Other genetic modifiers and environmental factors influence disease liability and CFTR-mutations alone should not be used to predict disease severity in CF [1,2,3,4,5]. Since the discovery of the Cystic Fibrosis Transmembrane Regulator (CFTR) gene in 1989 [6], more than 2000 mutations have been detected and reported in the CFTR1-database (CF Mutation Database) [7]. Not all of these variants are disease-causing.
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