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

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2022 Sep 20

PMID 36124617

Authors

Esra Yildiz Bolukbasi

Justyna A Karolak

Przemyslaw Szafranski

Tomasz Gambin

Nicholas Willard

Steven H Abman

Csaba Galambos

John P Kinsella

Pawel Stankiewicz

Affiliations

Soon will be listed here.

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.

Citing Articles

Analysis of copy number variations and possible candidate genes in spontaneous abortion by copy number variation sequencing.

Bai W, Zhang Q, Lin Z, Ye J, Shen X, Zhou L Front Endocrinol (Lausanne). 2023; 14:1218793.

PMID: 37916154 PMC: 10616874. DOI: 10.3389/fendo.2023.1218793.

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.

Yildiz Bolukbasi E, Karolak J, Szafranski P, Gambin T, Willard N, Abman S Mol Genet Genomic Med. 2022; 10(11):e2062.

PMID: 36124617 PMC: 9651602. DOI: 10.1002/mgg3.2062.

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