A recurrent 8 bp frameshifting indel in FOXF1 defines a novel mutation hotspot associated with alveolar capillary dysplasia with misalignment of pulmonary veins

Am J Med Genet A. 2019 Nov;179(11):2272-2276. doi: 10.1002/ajmg.a.61338. Epub 2019 Aug 22.


Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disease. Affected infants manifest with severe respiratory distress and refractory pulmonary hypertension and uniformly die in the first month of life. Heterozygous point mutations or copy-number variant deletions involving FOXF1 and/or its upstream lung-specific enhancer on 16q24.1 have been identified in the vast majority of ACDMPV patients. We have previously described two unrelated families with a de novo pathogenic frameshift variant c.691_698del (p.Ala231Argfs*61) in the exon 1 of FOXF1. Here, we present a third unrelated ACDMPV family with the same de novo variant and propose that a direct tandem repeat of eight consecutive nucleotides GCGGCGGC within the ~4 kb CpG island in FOXF1 exon 1 is a novel mutation hotspot causative for ACDMPV.

Keywords: FOXF1 haploinsufficiency; CpG island; recurrent mutation; tandem repeats.

Publication types

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

MeSH terms

  • Comparative Genomic Hybridization
  • CpG Islands / genetics
  • Enhancer Elements, Genetic
  • Female
  • Forkhead Transcription Factors / genetics*
  • Frameshift Mutation / genetics
  • Haploinsufficiency / genetics
  • Heterozygote
  • Humans
  • INDEL Mutation / genetics
  • Infant
  • Infant, Newborn
  • Male
  • Persistent Fetal Circulation Syndrome / diagnostic imaging
  • Persistent Fetal Circulation Syndrome / genetics*
  • Persistent Fetal Circulation Syndrome / pathology
  • Pulmonary Alveoli / abnormalities*
  • Pulmonary Alveoli / diagnostic imaging
  • Pulmonary Alveoli / pathology
  • Pulmonary Veins / diagnostic imaging
  • Pulmonary Veins / pathology*
  • Sequence Deletion
  • Tandem Repeat Sequences / genetics


  • FOXF1 protein, human
  • Forkhead Transcription Factors

Supplementary concepts

  • Alveolar capillary dysplasia