LAUSR

RATIONALE Variants within the cystic fibrosis transmembrane conductance regulator gene (CFTR) that are of unknown significance or are categorized as non CF-causing may be observed in persons with CF. These variants are frequently detected in children with inconclusive newborn screen results and, in some cases, may be associated with a benign presentation in early childhood that progresses to a CF phenotype later in life. OBJECTIVES To analyze data from individuals enrolled in the U.S. CF Foundation patient registry who have received a diagnosis of CF and who have variants found in a population of children with cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). METHODS This retrospective review analyzed registry data from individuals with a diagnosis of CF who also harbor one or more variants of interest due to their frequency within a CFSPID population and/or their interpretation as non CF-causing. Three groups were defined by the number of CF-causing (CF-C) variants identified (CF-Cx2, CF-Cx1, and CF-Cx0), which were reported in addition to variant(s) of interest. Multivariate quantile regression modeling of FEV1 outcome generated a disease severity score for each person determined by six selected variables. Median scores were calculated for the three groups. RESULTS Patients carrying one CF-causing variant and at least one variant of interest (CF-Cx1) had higher median disease severity score compared to CF-Cx2, suggesting milder phonotype (p<0.05). However, there was no statistically significant difference in scores between CF-Cx2 and the two other groups combined (CF-Cx1 and CF-Cx0; p=0.33). Analysis revealed that the CF-Cx1 and CF-Cx0 groups, when compared to the CF-Cx2 group, had later median diagnoses (8 years vs. newborn; p<0.0001), lower median sweat chloride (48 vs. 94.5 mmol/L, p<0.0001), lower prevalence of pancreatic insufficiency (29% vs. 78%; p<0.0001), and higher median FEV1% predicted (95% vs. 87%; p=0.0002). CONCLUSIONS Individuals with CF who have specific variants frequently identified in children with CFSPID have a similar range of disease severity scores compared to those who have two CF-causing variants, but a milder phenotype overall. Variants that should be given careful scrutiny due to their high prevalence are: G576A+R668C, T854T, R75Q, F1052V, R1070W, R31C, and L967S.