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
11078474 Fang et al. 2000: Describe a nonsense mutation and a frameshift mutation predicted to result in premature truncation in two unrelated families with lymphedema-distichiasis (LD) syndrome. The phenotype was variable amongst all affected family members. Two carrier individuals in family 1 (with the nonsense mutation) were fetuses electively terminated due to hydrops fetalis. The proband of the second family (frameshift mutation) was found to have the "additional features of cystic hygroma, arachnoid cysts, and cleft palate." The authors proposed that their features were due to haploinsufficiency of FOXC2, though no functional studies were performed.
11694548 Erickson et al. 2001: Describe 5 additional families with LD syndrome and mutations in FOXC2, including two novel nonsense mutations.
21918810 de Bruyn et al. 2012: A nonsense mutation was identified in a newborn girl who had hydrops and severe pulmonary lymphangiectasia. This was inherited from her father who had distichiasis and adult-onset lymphedema.

Haploinsufficiency phenotype comments:

From GeneReviews (please see for more information): "Lymphedema-distichiasis syndrome is characterized by lower-limb lymphedema and distichiasis (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair). Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis than females. Distichiasis, which may be present at birth, is observed in 94% of affected individuals. About 75% of affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include varicose veins, congenital heart disease, and ptosis. About 25% of individuals are asymptomatic." "No whole-gene deletions have been reported...The assumed mechanism of pathogenesis is haploinsufficiency. It is not clear whether the frameshift mutations produce a protein product with novel amino acids or whether the mRNA or proteins are degraded. " Additionally, non-focal deletions that encompass FOXC2 have been reported (PMID: 23074687 and 22407726) and the phenotypes of these affected individuals have included cystic hygroma in one case and distichiasis in the other. Additional reports of mutations (including in/dels, frameshifts) in the context of Lymphedema-Distichiasis include PMIDs: 23747797, 22349027, 20552815, and 18986489).

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

Triplosensitivity phenotype comment:

Of note: "A duplication of a region 5? to FOXC2 has been shown in an isolated case with lymphedema distichiasis and no FOXC2 mutation [PMID: 20218083]. It is not known if the duplication has a causative effect." (GeneReviews)