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Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype

  • Przemyslaw Szafranski
  • Qian Liu
  • Justyna A. Karolak
  • Xiaofei Song
  • Nicole de Leeuw
  • Brigitte Faas
  • Romana Gerychova
  • Petr Janku
  • Marta Jezova
  • Iveta Valaskova
  • Kathleen A. Gibbs
  • Lea F. Surrey
  • Virginie Poisson
  • Denis Bérubé
  • Luc L. Oligny
  • Jacques L. Michaud
  • Edwina Popek
  • Paweł StankiewiczEmail author
Original Investigation

Abstract

Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases, FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activity of the remaining allele of the enhancer. Sequencing of these alleles revealed two rare SNVs, rs150502618-A and rs79301423-T, mapping to the partially overlapping binding sites for TFAP2s and CTCF in the core region of the enhancer. Moreover, in a family with three histopathologically-diagnosed ACDMPV siblings whose missense FOXF1 mutation was inherited from the healthy non-mosaic carrier mother, we have identified a rare SNV rs28571077-A within 2-kb of the above-mentioned non-coding SNVs in the FOXF1 enhancer in the mother, that was absent in the affected newborns and 13 unrelated ACDMPV patients with CNV deletions of this genomic region. Based on the low population frequencies of these three variants, their absence in ACDMPV patients, the results of reporter assay, RNAi and EMSA experiments, and in silico predictions, we propose that the described SNVs might have acted on FOXF1 enhancer as hypermorphs.

Notes

Acknowledgements

This work was supported by grants awarded by National Heart, Lung, and Blood Institute (NHLBI) Grant R01HL137203 to PSt and National Organization for Rare Disorders (NORD) Grant 16001 to PSz.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

439_2019_2073_MOESM1_ESM.docx (2 mb)
Supplementary material 1 (DOCX 2043 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Przemyslaw Szafranski
    • 1
  • Qian Liu
    • 1
  • Justyna A. Karolak
    • 1
    • 2
  • Xiaofei Song
    • 1
  • Nicole de Leeuw
    • 3
  • Brigitte Faas
    • 3
  • Romana Gerychova
    • 4
  • Petr Janku
    • 4
    • 5
  • Marta Jezova
    • 6
  • Iveta Valaskova
    • 7
  • Kathleen A. Gibbs
    • 8
  • Lea F. Surrey
    • 8
    • 9
  • Virginie Poisson
    • 10
    • 11
  • Denis Bérubé
    • 10
    • 11
  • Luc L. Oligny
    • 10
    • 12
  • Jacques L. Michaud
    • 10
    • 11
  • Edwina Popek
    • 13
  • Paweł Stankiewicz
    • 1
    Email author
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of Genetics and Pharmaceutical MicrobiologyPoznan University of Medical SciencesPoznanPoland
  3. 3.Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
  4. 4.Department of Obstetrics and GynecologyMasaryk University and University Hospital BrnoBrnoCzech Republic
  5. 5.Department of Nursing and MidwiferyMasaryk UniversityBrnoCzech Republic
  6. 6.Department of PathologyMasaryk University and University Hospital BrnoBrnoCzech Republic
  7. 7.Department of Medical GeneticsMasaryk University and University Hospital BrnoBrnoCzech Republic
  8. 8.Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  9. 9.Department of Pathology and Laboratory MedicinePerelman School of MedicinePhiladelphiaUSA
  10. 10.CHU Sainte-JustineMontrealCanada
  11. 11.Department of PediatricsUniversité de MontréalMontrealCanada
  12. 12.Department of PathologyUniversité de MontréalMontrealCanada
  13. 13.Department of Pathology and ImmunologyBaylor College of MedicineHoustonUSA

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