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REFINEMENT OF NEWBORN SCREENING FOR CYSTIC FIBROSIS WITH NEXT GENERATION SEQUENCING.

BACKGROUND
Newborn screening (NBS) for cystic fibrosis (CF) has been underway universally in the USA 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 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 cystic fibrosis 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 cystic fibrosis metabolic syndrome/cystic fibrosis 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. This article is protected by copyright. All rights reserved.