Novel CFTR Variants Identified during the First 3 Years of Cystic Fibrosis Newborn Screening in California

Abstract

California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.

Damaged goods?: an empirical cohort study of blood specimens collected 12 to 23 hours after birth in newborn screening in California

“…After a specimen's immunoreactive trypsinogen (IRT) assay (using immunofluorescence assay) is found elevated, it is further tested using the California cystic fibrosis transmembrane conductance regulator mutation panel. 22 A specimen with only one mutation identified on the California cystic fibrosis transmembrane conductance regulator mutation panel is then sent for cystic fibrosis transmembrane conductance regulator gene sequencing. For all the conditions tested, newborns with positive results are referred to a regional specialty-care follow-up center that coordinates the confirmatory diagnosis process; if a condition is confirmed, then the center provides ongoing clinical care for patients.…”

“…Although we analyzed initial IRT positive results for CF screening in the current study, it should be noted that specimens with elevated IRT were not called out as positive to the primary-care provider and were further tested with the California cystic fibrosis transmembrane conductance regulator mutation panel as mentioned above and are not counted as false positives. 22 Only 1 year of initial screening data (2013) was used for false-positive analysis because it provided sufficient power to detect significant differences between two collection-timing groups based on sample size calculation prior to the final data analysis. During the study period, some analyte cutoffs were modified as the result of adjustment to different testing kits and laboratory methods.…”

Geographic variations in cystic fibrosis: An analysis of the U.S. CF Foundation Registry

“…Due to the longer life expectancy, the prevalence of co‐morbid conditions in CF including CF‐related diabetes (CFRD) and depression has directly increased, complicating treatment regimens. Additionally, diagnostic advancements for CF‐causing mutations have led to the expanded identification of milder forms of CF which may require less aggressive treatment regimens, further complicating traditional treatment regimens based on more classic disease …”

Development of DNA Confirmatory and High-Risk Diagnostic Testing for Newborns Using Targeted Next-Generation DNA Sequencing

“…26,37 The cost of NBDx (Supplementary Note S2 online) is significantly less than that of WES, and both tests are expected to be similar in price range to diagnostic tests currently on the market and therefore should enable replacement of single-gene tests, as justified by delays and increased patient-management costs. 6,10,11 We established performance benchmarks supporting direct clinical use similar to WGS newborn/pediatric testing of Mendelian diseases.…”