Newborn Screening for Cystic Fibrosis in California

TLDR

This study reports on the first five years of California’s newborn cystic fibrosis screening program, describing its 3‑step immunoreactive trypsinogen and CFTR mutation testing strategy. The program used a 3‑step approach: measuring immunoreactive trypsinogen, testing 28–40 CFTR mutations in high‑level samples, and sequencing single‑mutation specimens, with infants having ≥2 mutations referred for care and single‑mutation carriers offered genetic counseling. In 2.57 million screened infants, the program identified 345 CF cases (prevalence 1/6899), 533 CFTR‑related metabolic syndrome cases, and 1,617 carriers, missed 28 CF cases, achieved 92 % sensitivity, 34 % PPV, and detected 303 mutations—including 78 novel variants—with a median referral age of 34 days and overall high detection and low false‑positive rates.

Abstract

This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California.From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling.Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively).The 3-step model had high detection and low false-positive levels in this diverse population.