ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Two phenotypes are associated with mutations in FTL, but neither of them are due to haploinsufficiency. Changes in the FTL gene have been associated with neuroferritinopathy (see GeneReview). At the time of evaluation, six different frameshift and one missense mutation have been reported amongst individuals and families diagnosed with neuroferritinopathy (PMID: 23814539 for review). These mutations tend to impact the C-terminus and lead to extended proteins. Evidence suggests that these mutations act in a dominant-negative manner (PMID: 20159981). Mutations specific to the iron-responsive-element (IRS) in FTL cause hereditary hyperferritinemia-cataract syndrome (HHCS). These mutations interfere with negative feedback by circulating iron and lead to constitutive trancription of FTL. From Kroger et al. (2011) (PMID:21936912): "In 1995, Bonneau et al. speculated that the reason for the accumulation of L-ferritin in HHCS is a mutation on the IRE [iron-responsive element] coding region of L-ferritin [1]. In 1995, two groups in Italy and France simultaneously described the first two point mutations in the IRE of L-ferritin gene [3,4]. These mutations all change the structure of the IRE in a way which reduces or abolishes binding to the IRP. This leads to unregulated translation of the L-ferritin gene and consequently elevated levels of circulating L-ferritin [1,3,12,14,15]."

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