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A2843 - Frequency of CFTR Mutations in Individuals Evaluated for Primary Ciliary Dyskinesia
Author Block: W. Hannah1, V. Gonzales2, G. Kithcart2, K. Nykamp3, K. Ouyang3, R. Truty3, M. Zeman3, N. Marozkina2, L. Smith2, E. Roesch2, C. Li4, M. Drumm5, B. Gaston2; 1Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, United States, 2Division of Pulmonology, Department of Pediatrics, Rainbow Babies and Children’s Hospital, University Hospitals Cleveland Medical Center, Cleveland, OH, United States, 3Invitae Corporation, San Francisco, CA, United States, 4Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States, 5Department of Genetics and Genome Sciences and Division of Pulmonology, Department of Pediatrics, Case Western Reserve University and Rainbow Babies and Children's Hospital and University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
Rationale: Heterozygous mutations in cystic fibrosis transmembrane conductance regulator (CFTR), the gene implicated in cystic fibrosis (CF), have been suggested to be a risk factor for asthma. We hypothesized that individuals who do not have a diagnostic result from primary ciliary dyskinesia (PCD) genetic testing may be more likely than a control population to be heterozygous for a CFTR mutation. Secondly, we hypothesized that individuals with a molecular diagnosis of PCD likely have the same prevalence of CFTR heterozygotes compared to a control population. Methods: Data were available from 1024 individuals who had PCD genetic testing and 91777 controls who had genetic testing through Invitae. Because CFTR was included on the platform for this testing, the rate of pathogenic CFTR mutations could be retrospectively studied. The common poly-thymidine variant, 5T, was stratified and analyzed separately as it is associated with a range of phenotypes with incomplete penetrance. Individuals who had genetic testing for PCD were categorized as positive or as non-diagnostic if testing was negative or uncertain. Prevalence of CFTR heterozygosity was then compared between the PCD positive individuals, the non-diagnostic cohort, and the control population. Results: Neither the PCD positive cohort nor individuals with non-diagnostic PCD genetic testing had a statistically different prevalence of CFTR heterozygosity compared to the control population. Notably, nearly 1% of individuals who had non-diagnostic genetic testing results for PCD had 2 pathogenic CFTR mutations (7 out of 854). This was an unexpected result that was dramatically different from the number of individuals with 2 pathogenic CFTR mutations in the PCD positive cohort (0 out of 162) and control population (16 out of 91777). Conclusions: Our study did not find an increased prevalence, compared to controls, of heterozygous CFTR carriers in either the cohort with non-diagnostic PCD genetic testing or the cohort with positive testing. Studying the CFTR carrier prevalence among individuals with PCD who are at the phenotypic extremes may be valuable for assessing whether CFTR genotype modifies PCD phenotype. We identified that roughly 1% of individuals who have a non-diagnostic genetic evaluation for PCD have two pathogenic CFTR mutations (by a conservative estimate given that 5T variants were not classified as pathogenic). This observation highlights the phenotypic overlap of PCD and CF and has an important implication. In individuals evaluated for PCD, particularly those with no situs abnormalities, the possibility of CF should be considered in the differential diagnosis.