CASE REPORT article
Front. Genet.
Sec. Pharmacogenetics and Pharmacogenomics
Pitfalls in CF screening – targeted variant analysis can cause misleading results and therapy recommendations
Provisionally accepted
- 1Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- 2Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany
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Abstract Background: Cystic Fibrosis (CF) is primarily diagnosed in Germany through newborn screening (NS) using immunoreactive trypsinogen (IRT)/Pancreatitis-Associated Protein (PAP) measurements and genetic testing for common CFTR gene variants. While this method is effective in identifying the most frequent mutations, it may overlook complex alleles, which can impact phenotype and treatment efficacy. Case Presentation: We report the case of a five-year-old girl diagnosed with CF through NS, initially identified as homozygous for the F508del variant. Despite early Orkambi therapy, her response was suboptimal, with high sweat chloride levels and recurrent respiratory infections. Re-sequencing with a next-generation sequencing (NGS) panel revealed an additional undetected heterozygous pathogenic variant. Upon switching to elexacaftor/tezacaftor/ivacaftor (ETI), sweat chloride levels significantly improved. Conclusion: Standard genetic screening methods may fail to detect complex alleles, leading to misinterpretation of genotype and suboptimal treatment choices. This case highlights the necessity of comprehensive genetic analysis in patients with unexpected therapy responses. When CFTR modulator therapy does not yield the expected improvements, re-sequencing should be considered to optimize precision medicine approaches for CF.
Keywords: complex allele, Newborn screening, Next-generation sequencing, CFTR modulators, CFTR (cystic fibrosis transmembrane regulator)
Received: 27 Aug 2025; Accepted: 19 Nov 2025.
Copyright: © 2025 Karnstedt, Ahting, Behrendt, Hove and Hentschel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maike Karnstedt, maike.karnstedt@medizin.uni-leipzig.de
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