Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant.

Abstract

Heterozygous single nucleotide variants (SNVs) or copy-number variant deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80-90% of patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe a four-generation family with a deceased ACDMPV neonate, her sibling from the electively terminated pregnancy, healthy mother with a history of pulmonary arterial hypertension (PAH), an unaffected aunt, an aunt deceased due to findings consistent with ACDMPV, and a reportedly unaffected grandmother, all with the frameshifting variant c.881_902dup (p.Gly302Profs*46) in FOXF1, and a deceased great-grandmother with a history of PAH. Genome sequencing analyses in the proband's unaffected mother revealed a non-coding putative regulatory SNV rs560517434-A within the lung-specific distant FOXF1 enhancer in trans to the FOXF1 frameshift mutation. Functional testing of this variant using an in vitro luciferase reporter assay showed that it increased FOXF1 promoter activity 10-fold. Our studies further demonstrate that non-coding SNVs in the FOXF1 enhancer region can rescue the lethal ACDMPV phenotype and support the compound inheritance gene dosage model.

• Authors: Esra Yıldız Bölükbaşı, Justyna A Karolak, Przemyslaw Szafranski, Tomasz Gambin, Admire Matsika, Sam McManus, Hamish S Scott, Peer Arts, Thuong Ha, Christopher P Barnett, Jonathan Rodgers, Paweł Stankiewicz
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 30 Issue 10 Pg. 1182-1186 (10 2022) ISSN: 1476-5438 [Electronic] England
• PMID: 35902696 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to European Society of Human Genetics.

Chemical References

• FOXF1 protein, human
• Forkhead Transcription Factors
• Nucleotides

Topics

• Female
• Forkhead Transcription Factors (genetics)
• Frameshift Mutation
• Humans
• Infant, Newborn
• Nucleotides
• Persistent Fetal Circulation Syndrome (genetics)
• Pulmonary Alveoli (abnormalities)
• Sequence Deletion