Expansion of Variant Panels in Newborn Screening Algorithms to Identify Cystic Fibrosis: A Retrospective Analysis of 25 Years of Genotypes and Implications on Diagnosis

Author Department

Pediatrics

Document Type

Article, Peer-reviewed

Publication Date

10-2025

Abstract

Purpose: We seek to understand the incremental value of applying expanded variant panels or sequencing in population-based screening algorithms for a well-understood condition like cystic fibrosis (CF). We compared newborn screening methods to determine at what point do attempts to increase sensitivity of second-tier testing meet diminishing returns.

Methods: Using the genotypes of all Massachusetts CF-affected patients who were born between February 1,1999 and January 31,2024, we retrospectively applied screening algorithms that used: (a) 39 CF gene (CFTR) variants, 139 CFTR variants, or CFTR sequencing, and (b) different algorithms for referral to CF Center. Sensitivity, specificity, and timing of diagnosis were evaluated.

Results: Our current 39 CFTR variant panel and referral algorithm yields a clinical sensitivity of 98.7%. In Massachusetts, expanding the variant panel might result in limited sensitivity improvement but if the referral algorithm requires detection of two CFTR variants, might decrease the sensitivity.

Conclusion: Expanding the CFTR variants genotyped does not necessarily guarantee an increase in screening sensitivity. Using a conservative cutoff for DNA testing might accomplish as much. Screening turn-around time, costs, and geographic location of CF Centers should be factored into decisions about the benefit of NGS technology within newborn screening.

Keywords: CFTR variant panels; Cystic Fibrosis; Newborn screening; Next Generation Sequencing.

PMID

41176686

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