Esra Yıldız Bölükbaşi, Tomasz Gambin, Justyna A. Karolak, Nicholas Willard, Przemyslaw Szafranski, Steven H. Abman, Csaba Galambos, John P. Kinsella, Paweł Stankiewicz
Baylor College of Medicine. Poznan University of Medical Sciences. Warsaw University of Technology. University of Colorado Anschutz Medical Campus.
United States and Poland
Molecular Genetics and Genomic Medicine
Mol Genet Genomic Med 2022; 10:
DOI: 10.1002/mgg3.2062
Abstract
Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) results from haploinsufficiency of the mesenchymal transcription factor FOXF1 gene. To date, only one case of an ACDMPV-causative CNV deletion inherited from a very-low level somatic mosaic mother has been reported.
Methods: Clinical, histopathological, and molecular studies, including whole genome sequencing, chromosomal microarray analysis, qPCR, and Sanger sequencing, followed by in vitro fertilization (IVF) with preimplantation genetic testing (PGT) were used to study a family with a deceased neonate with ACDMPV.
Results: A pathogenic CNV deletion of the lung-specific FOXF1 enhancer in the proband was found to be inherited from an unaffected mother, 36% mosaic for this deletion in her peripheral blood cells. The qPCR analyses of saliva, buccal cells, urine, nail, and hair samples revealed 19%, 18%, 15%, 19%, and 27% variant allele fraction, respectively, indicating a high recurrence risk. Grandparental studies revealed that the deletion arose on the mother’s paternal chromosome 16. PGT studies revealed 44% embryos with the deletion, reflecting high-level germline mosaicism.
Conclusion: Our data further demonstrate the importance of parental testing in ACDMPV families and reproductive usefulness of IVF with PGT in families with high-level parental gonosomal mosaicism.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Class III. Pulmonary Hypertension Associated with Developmental Diseases of the Lung
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes