Findings Spectrum from Comprehensive CFTR Gene Sequencing in Reproductive and Clinical Settings: A Retrospective Analysis of 834 Consecutive Cases

Background: Comprehensive CFTR gene analysis by next-generation sequencing (NGS) enables the detection of a broad spectrum of CFTR variants, including variants associated with cystic fibrosis (CF), CFTR-related disorders (CFTR-RD), and variants of uncertain significance (VUS). However, data describing the real-world application of comprehensive CFTR sequencing in Southern European populations remain limited. Methods: This retrospective study included 834 consecutive individuals who underwent comprehensive CFTR gene sequencing between 2018 and 2024 in two diagnostic molecular genetics laboratories in Greece. The cohort comprised 32 prenatal and 802 postnatal samples referred for various clinical and reproductive indications. Variant interpretation was based on CFTR-specific databases, published evidence, and laboratory assessment. Results: CFTR findings were identified in 141 of the 834 individuals (16.9%). CF-causing variants were identified in 36 individuals (4.3%), CFTR-RD-associated variants in 42 (5.0%), and VUS in 50 (6.0%). Thirteen individuals (1.6%) carried two different CFTR variants and were analyzed as a separate, mutually exclusive category. Routine carrier screening was the most common referral indication (67.9%), followed by IVF/reproductive planning (15.7%). Conclusions: This study describes the spectrum of CFTR findings identified through comprehensive sequencing in a Greek cohort undergoing reproductive and clinical testing. The findings highlight the diversity of CFTR variants encountered in routine practice and the importance of careful variant interpretation and genetic counseling.