Journal Article

Fast detection of FOXF1 variants in patients with alveolar capillary dysplasia with misalignment of pulmonary veins using targeted sequencing

van Marion, Ronald, Tibboel, Dick, Magielsen, Frank, Post, Martin, Debeer, Anne, van Heijst, Arno, von der Thüsen, Jan H., Slot, Evelien, de Klein, Annelies, Dubbink, Hendrikus J., Rottier, Robbert J.

2021

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 3' Untranslated Regions - genetics / 5' Untranslated Regions - genetics / Abnormalities, Multiple - genetics / Basic Science Article / Biopsy / Congenital diseases / Deoxyribonucleic acid / DNA / DNA Copy Number Variations / DNA Mutational Analysis - methods / Exons - genetics / Extracorporeal membrane oxygenation / Female / Fibroblasts - chemistry / Forkhead Transcription Factors - genetics / Gene Duplication / Genomes / High-Throughput Nucleotide Sequencing - methods / Humans / Infant / Infant, Newborn / Lung - chemistry / Lung diseases / Male / Medical diagnosis / Medicine / Medicine & Public Health / Mutation / Pediatric Surgery / Pediatrics / Persistent Fetal Circulation Syndrome - genetics / Polymorphism, Single Nucleotide / Protein Isoforms - genetics / Pulmonary hypertension / Sequence Deletion / Unnecessary Procedures / Veins & arteries