ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23505205 Sen et al. 2013: Describes variants detected amongst a sample of over 90 infants with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), including 9 different nonsense and 7 frameshift mutations. Many of the infants had associated cardiac, intestinal, or urinary tract malformations. This paper also includes a review of mutations (1 nonsense and 2 frameshift) previously reported by some of the authors (Stankiewicz et al, PMID:19500772). The authors state that the identified mutations are not reported in the dbSNP and are not cited in the Exome Variant Server, NHLBI Exome Sequencing Project, Seattle, WA (URL:, that covers more than 10,000 alleles. The authors report four familial cases of missense mutations, of which three show maternal inheritance, consistent with paternal imprinting of the gene (further described in PMID: 22990143)

Haploinsufficiency phenotype comments:

In addition to the frameshift and nonsense mutations reported in the Stankiewicz and Sen papers, several patients with deletions have been reported which provide strong supportive evidence of haploinsufficiency for FOXF1 as the cause of ACD/MPV (Stankiewicz et al, PMID: 19500772 and Yu et al, PMID: 20425831). Finally, one other report was available for review of a newborn with ACD/MPV who had a de novo frameshift mutation (Castilla-Fernandez, PMID: 23624968). The exact mutation was not provided in the paper and testing was done at one of the laboratories that published the Sen paper. Therefore, we can't be sure that this patient was not also included in that cohort. While it is optimal to have reports of mutations from independent groups, ACD/MVP is a very rare condition and only two laboratories currently offer testing for FOXF1 in the world. These two laboratories were involved with a large consortium of clinical sites to publish the Sen paper and the supporting deletion data comes from additional groups.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity