Maternal mutations of FOXF1 cause alveolar capillary dysplasia despite not being imprinted

Hum Mutat. 2017 Jun;38(6):615-620. doi: 10.1002/humu.23213. Epub 2017 Mar 24.


Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare cause of pulmonary hypertension in newborns. Maternally inherited point mutations in Forkhead Box F1 gene (FOXF1), deletions of the gene, or its long-range enhancers on the maternal allele are responsible for this neonatal lethal disorder. Here, we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. Since this parental transmission is consistent with genomic imprinting, the parent-of-origin specific monoallelic expression of genes, we have undertaken a detailed analysis of both allelic expression and DNA methylation. FOXF1 and its neighboring gene FENDRR were both biallelically expressed in a wide range of fetal tissues, including lung and intestine. Furthermore, detailed methylation screening within the 16q24.1 regions failed to identify regions of allelic methylation, suggesting that disrupted imprinting is not responsible for ACDMPV.

Keywords: FOXF1; alveolar capillary dysplasia; imprinting; methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Comparative Genomic Hybridization
  • DNA Methylation / genetics
  • Female
  • Forkhead Transcription Factors / genetics*
  • Genomic Imprinting*
  • Humans
  • Hypertension, Pulmonary
  • Infant, Newborn
  • Maternal Inheritance / genetics
  • Mutation
  • Persistent Fetal Circulation Syndrome / complications
  • Persistent Fetal Circulation Syndrome / genetics*
  • Persistent Fetal Circulation Syndrome / pathology
  • Pregnancy
  • Pulmonary Alveoli / abnormalities*
  • Pulmonary Alveoli / pathology
  • Twins, Monozygotic


  • FOXF1 protein, human
  • Forkhead Transcription Factors

Supplementary concepts

  • Alveolar capillary dysplasia