NYMC Faculty Publications

Characterization of 223 Infants With CFTR-Related Metabolic Syndrome/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) Identified During the First Three Years of Newborn Screening via IRT-DNA-SEQ in New York State

Author Type(s)

Faculty

DOI

10.1016/j.jcf.2024.10.015

Journal Title

Journal of Cystic Fibrosis

First Page

404

Last Page

411

Document Type

Article

Publication Date

3-1-2025

Department

Pediatrics

Keywords

CF conversion, CFTR sequencing, Cystic fibrosis screen positive, Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS), inconclusive diagnosis (CFSPID), IRT-DNA-SEQ newborn screening algorithm, sweat chloride trends

Disciplines

Medicine and Health Sciences

Abstract

Background: New York State implemented CFTR gene sequencing into the Cystic Fibrosis newborn screening (CF NBS) algorithm on 12/1/2017 to reduce false positive screens. With addition of sequencing, infants with 2 CFTR variants but low or intermediate sweat chloride levels classified as CFTR-related metabolic syndrome/CF screen-positive, inconclusive diagnosis (CRMS/CFSPID) are identified at a higher frequency, posing challenges to clinicians and families. Methods: Data from 375 screen-positive newborns between 12/1/2017 and 11/30/2020 were analyzed. We summarized 1–3 years of clinical follow-up for babies with CRMS/CFSPID following implementation of the IRT-DNA-SEQ algorithm. Results: Among 375 newborns referred, 223 (59.5 %) were classified as CRMS/CFSPID. Overall, 195/223 (87.4 %) had a CF-causing/pathogenic/likely pathogenic CFTR variant and a variant of varying clinical consequence (VCC) or uncertain significance (VUS). The most common VCC or VUS was 5T-12TG [n = 90/223 (40 %)]. All initial and repeat sweat chloride test (SCT) values for this cohort were <60 mmol/L after 1–3 years follow-up. Ninety-nine infants had ≥1 repeat SCT. Forty-two (18.8 %) had ≥1 SCT in the intermediate range (30–59 mmol/L) and 181 (81.2 %) were <30 mmol/L. Twenty-nine infants had sweat chloride increasing ≥5 mmol/L per year (29.3 % of infants with repeat testing). Fecal elastase was reported for 114/223 infants; none were abnormal. There were no conversions to CF during the 3-year follow-up period, however 2 infants have subsequently converted with diagnostic SCTs. Conclusions: The New York experience may help inform updates to clinical guidelines, which are needed to optimize care, management, counseling, and long-term follow-up of infants and children with CRMS/CFSPID.

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