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


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.

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Fig. 1: Pedigree of the four-generation family and results of the luciferase reporter assay.
Fig. 2: Schematic representation of the proposed model of in cis regulation of FOXF1 expression by its ~60 kb upstream lung-specific enhancer.

Data availability

This variant has been submitted to the ClinVar database under the submission number SUB10968355. The data that support this study are available from the corresponding author upon reasonable request.


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We would like to thank Dr. E. Popek for the histopathological evaluations and the family for participating and supporting this study.


Design of the study and collection, analysis, and interpretation of data were supported by grant awarded by the US National Institutes of Health (NIH), National Heart Lung and Blood Institute (NHLBI) R01HL137203 (PS). The Genomic Autopsy Study research was supported by NHMRC grant (APP1123341), Genomics Health Futures Mission—Medical Research Futures Fund (GHFM76777), and the Australian Genomic Health Alliance NHMRC Targeted Call for Research into Preparing Australia for the Genomics Revolution in Healthcare (GNT1113531) (HS and CB). PA was supported by fellowships from The Hospital Research Foundation and the Royal Adelaide Hospital Research Foundation.

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Authors and Affiliations



EYB executed the experiments; EYB, PSz, JAK, TG, PS analyzed and interpreted the data; AM did the histopathalogical evaluations; SM, HSS, PA, TH, CPB and JR provided clinical material; SM, AM, HSS, PA, TH, CPB and JR interpreted and described clinical findings; EYB, JAK, PS wrote the manuscript; all authors reviewed and discussed the manuscript during preparation and approved the final manuscript.

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Correspondence to Paweł Stankiewicz.

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The authors declare no competing interests.

Ethical approval

The initial diagnosis in the proband was performed as part of the NHMRC and GHFM-MRFF funded Genomic Autopsy Study and was approved by the Human Ethics Committee of the Women’s and Children’s Health Network, South Australia, Australia (HREC/15/WCHN/35) and the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. Informed consent for genomic analysis and participation in study protocols was obtained from parents, and all research was conducted in accordance with the Declaration of Helsinki. The study research protocols were approved by the Institutional Review Board for Human Subject Research at Baylor College of Medicine (H-8712). Informed consent was obtained from all participants prior to genetic testing.

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Yıldız Bölükbaşı, E., Karolak, J.A., Szafranski, P. et al. Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant. Eur J Hum Genet (2022).

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