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Review
. 2025 Jul 30;11(3):60.
doi: 10.3390/ijns11030060.

Refining CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Diagnosis: Impact of CFTR2 Variant Classifications

MacKenzie Wyatt  1   2 , Alexandra Quinn  1   2 , Lincoln Shade  3 , Meghan McGarry  1   2
Affiliations
Review

Refining CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Diagnosis: Impact of CFTR2 Variant Classifications

MacKenzie Wyatt et al. Int J Neonatal Screen. .

Abstract

An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS who do not meet the diagnostic criteria for CF (two CF-causing variants and/or sweat chloride > 60 mmol/L). This indeterminate diagnosis is called cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID occurs when it is not clearly known whether CFTR variants are disease-causing. In 2024, the CFTR2 classification of many CFTR variants was changed from unknown significance to either CF-causing variants or variants of varying clinical consequences (VVCCs). We conducted a meta-analysis of CRMS/CFSPID cases from manuscripts to describe how the diagnoses would change using two different variant panels: (1) only CF-causing CFTR variants (PanelCF-causing) and (2) CF-causing variants and VVCCs (PanelCF-causing+VVCCs). Using the PanelCF-causing, 8.7% had two CF-causing variants (reclassified as CF), while 91.3% had less than two CF-causing variants (reclassified as Undetected). Using the PanelCF-causing+VVCCs, 51.4% had either two VVCCs or one VVCC with one CF-causing variant detected (reclassified as CRMS/CFSPD), 39.9% had less than two CF-causing variants detected (reclassified as Undetected), and 8.7% had two CF-causing variants (reclassified as CF). In conclusion, using the updated CFTR2 classification of CFTR variants significantly decreases the number of children with CRMS/CFSPID and gives a definitive diagnosis of CF to some children while not detecting as many children who are unlikely to develop CF.

Keywords: CF screen positive inconclusive diagnosis; CFSPID; CRMS; CRMS/CFSPID; cystic fibrosis; cystic fibrosis transmembrane conductance regulator gene; cystic fibrosis transmembrane conductance regulator-related metabolic syndrome; genetic testing; newborn screening; sweat chloride.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
PRISMA flow diagram of literature review.
Figure 2
Figure 2
Reclassification Diagnoses of CRMS/CFSPID cases reported in the literature using 2 Variant Panels: (a) reclassification diagnosis using PanelCF-causing eliminates CRMS/CFSPID diagnoses; (b) reclassification diagnosis using PanelCF-causing+VVCCs retains more children with CRMS/CFSPID and misses less children who convert to CF.
Figure 3
Figure 3
Initial sweat chloride by reclassification diagnosis from PanelCF-causing+VVCCs. *** Statistical significance p-value < 0.05.
See this image and copyright information in PMC

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