Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal congenital lung disorder associated with heterozygous variants in the FOXF1 gene or its regulatory region. Patients with ACD/MPV unnecessarily undergo invasive and expensive treatments while awaiting a diagnosis. The aim of this study was to reduce the time to diagnose ACD/MPV by developing a targeted next-generation sequencing (NGS) panel that detects FOXF1 variants. Methods: A FOXF1-targeted NGS panel was developed for detection of mutations and large genomic alterations and used for retrospective testing of ACD/MPV patients and controls. Results were confirmed with Sanger sequencing and SNP array analysis. Results: Each amplicon of the FOXF1-targeted NGS panel was efficiently sequenced using DNA isolated from blood or cell lines of 15 ACD/MPV patients and 8 controls. Moreover, testing of ACD/MPV patients revealed six novel and six previously described pathogenic or likely pathogenic FOXF1 alterations. Conclusion: We successfully designed a fast and reliable targeted genetic test to detect variants in the FOXF1 gene and its regulatory region in one run. This relatively noninvasive test potentially prevents unnecessary suffering for patients and reduces the use of futile and expensive treatments like extra-corporeal membrane oxygenation. Impact: FOXF1-targeted NGS potentially prevents ACD/MPV patients from unnecessary suffering and expensive treatments.FOXF1-targeted NGS potentially reduces the number of misdiagnosis in ACD/MPV patients.Retrospective testing of ACD/MPV patients using FOXF1-targeted NGS revealed six novel pathogenic or likely pathogenic variants.

dx.doi.org/10.1038/s41390-020-0931-5, hdl.handle.net/1765/127381
Pediatric Research: international journal of human developmental biology
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Department of Clinical Genetics

Slot, E. (Evelien), von der Thusen, J.H, van Heijst, A.F.J, van Marion, R, Magielsen, F. (Frank), Dubbink, H.J, … de Klein, A. (2020). Fast detection of FOXF1 variants in patients with alveolar capillary dysplasia with misalignment of pulmonary veins using targeted sequencing. Pediatric Research: international journal of human developmental biology. doi:10.1038/s41390-020-0931-5