Narrowing the FOXF1 distant enhancer region on 16q24.1 critical for ACDMPV

Clin Epigenetics. 2016 Nov 3;8:112. doi: 10.1186/s13148-016-0278-2. eCollection 2016.


Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder caused by heterozygous point mutations or genomic deletions involving FOXF1 or its 60-kb tissue-specific enhancer region mapping 270 kb upstream of FOXF1 and involving fetal lung-expressed long non-coding RNA genes and CpG-enriched sites. Recently, we have proposed that the FOXF1 locus at 16q24.1 may be a subject of genomic imprinting.

Findings: Using custom-designed aCGH and Sanger sequencing, we have identified a novel de novo 104 kb genomic deletion upstream of FOXF1 in a patient with histopathologically verified full phenotype of ACDMPV. This deletion allowed us to further narrow the FOXF1 enhancer region and identify its critical 15-kb core interval, essential for lung development. This interval harbors binding sites for lung-expressed transcription factors, including GATA3, ESR1, and YY1, and is flanked by the lncRNA genes and CpG islands. Bisulfite sequencing of one of these CpG islands on the non-deleted allele showed that it is predominantly methylated on the maternal chromosome 16.

Conclusions: Substantial narrowing and bisulfite sequencing of the FOXF1 enhancer region on 16q24.1 provided new insights into its regulatory function and genomic imprinting.

Keywords: Copy-number variants; Genomic imprinting; Transcriptional enhancer.

Publication types

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

MeSH terms

  • Binding Sites
  • Chromosomes, Human, Pair 16 / genetics*
  • Comparative Genomic Hybridization
  • CpG Islands
  • Enhancer Elements, Genetic*
  • Estrogen Receptor alpha / genetics
  • Female
  • Forkhead Transcription Factors / chemistry
  • Forkhead Transcription Factors / genetics*
  • GATA3 Transcription Factor / genetics
  • Genomic Imprinting
  • Humans
  • Infant, Newborn
  • Male
  • Persistent Fetal Circulation Syndrome / genetics*
  • RNA, Long Noncoding / genetics*
  • Sequence Analysis, DNA / methods
  • Sequence Deletion*
  • YY1 Transcription Factor / genetics


  • ESR1 protein, human
  • Estrogen Receptor alpha
  • FOXF1 protein, human
  • Forkhead Transcription Factors
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • RNA, Long Noncoding
  • YY1 Transcription Factor
  • YY1 protein, human