Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development

J Med Genet. 2020 May;57(5):296-300. doi: 10.1136/jmedgenet-2019-106095. Epub 2019 Oct 29.


Background: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor FOXF1, which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype.

Methods: We analysed primary lung tissue from an infant with classic clinical and histological findings of ACDMPV and harboured a 340 kb deletion on chromosome 16q24.1 located 250 kb upstream of FOXF1.

Results: In RNA generated from paraffin-fixed lung sections, our patient had lower expression of FOXF1 than age-matched controls. He also had an abnormal pattern of FOXF1 protein expression, with a dramatic loss of FOXF1 expression in the lung. To gain insights into the mechanisms underlying these changes, we assessed the epigenetic landscape using chromatin immunoprecipitation, which demonstrated loss of histone H3 lysine 27 acetylation (H3K27Ac), an epigenetic mark of active enhancers, in the region of the deletion.

Conclusions: Together, these data suggest that the deletion disrupts an enhancer responsible for directing FOXF1 expression in the developing lung and provide novel insights into the mechanisms underlying a fatal developmental lung disorder.

Keywords: copy-number; epigenetics; microarray; other respiratory medicine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromosomes, Human, Pair 16 / genetics
  • Enhancer Elements, Genetic / genetics
  • Forkhead Transcription Factors / genetics*
  • Gene Deletion
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Haploinsufficiency / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Lung / growth & development
  • Lung / metabolism*
  • Lung / pathology
  • Persistent Fetal Circulation Syndrome / genetics*
  • Persistent Fetal Circulation Syndrome / pathology


  • FOXF1 protein, human
  • Forkhead Transcription Factors