Beyond Carrier Status: CFTR Heterozygosity as an Overlooked Clinical Risk Factor for Pancreatitis.

Abstract

This study assessed the effect of CFTR pathogenic variant status, detected during prenatal carrier screening, for the incidence and clinical recognition of cystic fibrosis-related phenotypes. Data were queried from the Vanderbilt University Medical Center clinical genetic database (CGdb), which includes clinically reported pathogenic variants and electronic health records (EHRs) from 2001 to 2023. Based on carrier screening results, we identified individuals heterozygous for a pathogenic CFTR variant and those who tested negative. Logistic regression tested associations between CFTR carrier status and 11 cystic fibrosis (CF)-related phenotypes. A phenome-wide association study (PheWAS) was performed to identify additional phenotypic associations, and manual chart review was conducted to evaluate recognition and clinical application of CFTR carrier status in patients diagnosed with pancreatitis. Among 12,082 women tested, CFTR carriers (n = 451) were at significantly higher risk of developing acute pancreatitis (p = 3.93 × 10^-6; OR = 4.68 [2.43-9.00]). No other CF-related phenotypes were significantly associated in this female cohort. Manual chart review revealed that CFTR carrier screening results were not clinically correlated with pancreatitis diagnoses. In this large cohort of women tested for prenatal carrier screening, CFTR pathogenic variants relevant to pancreatitis were overlooked, despite informing etiology, management, and prognosis.