Refinement of newborn screening for cystic fibrosis with next generation sequencing. Pediatr Pulmonol 2023 Mar;58(3):778-787
Date
11/24/2022Pubmed ID
36416003DOI
10.1002/ppul.26253Scopus ID
2-s2.0-85143973852 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
BACKGROUND: Newborn screening for cystic fibrosis (CF) has been underway universally in the United States for more than a decade, as well in most European countries, and algorithms have been evolving throughout this period with quality improvement projects as immunoreactive trypsinogen (IRT) determinations alone have been transformed to a 2-tier strategy with DNA analyses.
OBJECTIVE: To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the CF transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings.
DESIGN: Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes.
RESULTS: After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2-variants detected through screening, but for every CF case there were 1.4 with CF metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2-variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF.
CONCLUSION: NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2-variants during the screening process.
Author List
Rock MJ, Baker M, Antos N, Farrell PMAuthor
Nicholas Antos MD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cystic FibrosisCystic Fibrosis Transmembrane Conductance Regulator
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Infant
Infant, Newborn
Mutation
Neonatal Screening
Trypsinogen
