The purpose of newborn screening is early detection of inborn conditions for which prompt treatments mitigate mortality or irreversible damage. The first heritable immune disorders to which newborn screening has been applied are those that together comprise severe combined immunodeficiency (SCID), caused by defects in any of a diverse group of gene products essential for development of adaptive immunity provided by T and B lymphocytes.^1,2 A feature of all SCID is defective production of T cells. In most SCID, B cells are also defective, but even normal B cells cannot produce antibodies without T-cell help. Thus, infants with SCID are susceptible to life-threatening infections. Early detection and treatment optimize survival.^3-5 Provided that SCID is diagnosed before infections become overwhelming, affected infants can be rescued with hematopoietic stem cell transplantation; gene therapy; or, for adenosine deaminase deficiency, enzyme replacement therapy.^2,5-8

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: The 3-step model had high detection and low false-positive levels in this diverse population.