Fast detection of FOXF1 variants in patients with alveolar capillary dysplasia with misalignment of pulmonary veins using targeted sequencing
- 15 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Pediatric Research
- Vol. 89 (3), 518-525
- https://doi.org/10.1038/s41390-020-0931-5
Abstract
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 targeted NGS potentially prevents ACD/MPV patients from unnecessary suffering and expensive treatments. -targeted NGS potentially reduces the number of misdiagnosis in ACD/MPV patients. Retrospective testing of ACD/MPV patients using -targeted NGS revealed six novel pathogenic or likely pathogenic variants.Keywords
This publication has 26 references indexed in Scilit:
- Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspectsPulmonary Circulation, 2018
- Narrowing the FOXF1 distant enhancer region on 16q24.1 critical for ACDMPVClinical Epigenetics, 2016
- Long-range enhancers modulate Foxf1 transcription in blood vessels of pulmonary vascular networkHistochemistry and Cell Biology, 2016
- Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veinsHuman Genetics, 2016
- Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and DiseaseCurrent Genomics, 2015
- Pulmonary vascular development goes awry in congenital lung abnormalitiesBirth Defects Research Part C: Embryo Today: Reviews, 2014
- Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other MalformationsAmerican Journal of Human Genetics, 2009
- Expanding the phenotype of alveolar capillary dysplasia (ACD)The Journal of Pediatrics, 2004
- Open lung biopsy in neonatal and paediatric patients referred for extracorporeal membrane oxygenation (ECMO)Thorax, 2004
- Alveolar capillary dysplasia: Report of a case of prolonged life without extracorporeal membrane oxygenation (ECMO) and review of the literatureEarly Human Development, 2000