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. 2022 Nov;10(11):e2062.
doi: 10.1002/mgg3.2062. Epub 2022 Sep 20.

High-level gonosomal mosaicism for a pathogenic non-coding CNV deletion of the lung-specific FOXF1 enhancer in an unaffected mother of an infant with ACDMPV

Esra Yıldız Bölükbaşı  1 , Justyna A Karolak  2 , Przemyslaw Szafranski  1 , Tomasz Gambin  3 , Nicholas Willard  4 , Steven H Abman  5 , Csaba Galambos  4   5 , John P Kinsella  5 , Paweł Stankiewicz  1
Affiliations

High-level gonosomal mosaicism for a pathogenic non-coding CNV deletion of the lung-specific FOXF1 enhancer in an unaffected mother of an infant with ACDMPV

Esra Yıldız Bölükbaşı et al. Mol Genet Genomic Med. 2022 Nov.

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.

Keywords: genetics of lung development; germline mosaicism; parental mosaicism; somatic mosaicism.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
(a) Low‐power examination of the lung shows global immaturity with diffusely enlarged alveoli and mildly thick interstitium. Markedly dilated pulmonary vessels surrounding the bronchoarterial bundles (circle) are clearly visible. (b) At higher power view disordered circulatory elements including thickened pulmonary artery (PA) and dilated dysplastic capillaries located in the middle of the interstitium lacking connections with type 1 pneumocytes (green arrow) are seen. Surrounding and within the bronchoarterial bundle, markedly dilated and congested bronchial vasculature, including thin‐walled bronchial veins (BV) and microvessels (black arrows) are noted.
FIGURE 2
FIGURE 2
Variant allele fraction measured by qPCR in the mother's blood, saliva, buccal swab, urine, hair, and nail tissues compared to the proband's blood tissue
See this image and copyright information in PMC

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