ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17804835 Multigenerational Swiss family with dopa-responsive dystonia was found to have a partial gene deletion associated with the disease. The authors conclude that haploinsufficiency is a cause of the disorder and dosage studies should be done in addition to sequencing to rule out large rearrangements in this gene.
17111153 Authors detect a complete gene deletion as well as partial gene deletions in three families. When investigating families with dopa-responsive dystonia, the authors suggest MLPA analysis should be done. In another report, PMID: 22976901, a 24Kb promoter deletion led to a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family.
21287604 Affected family members were found, through sequencing of mRNA, to have a direct duplication of exon 2 of GCH1. Patients had onset of dopa-responsive dystonia in their teens.

Haploinsufficiency phenotype comments:

Mutations in GCH1 lead to dopa responsive dystonia (DRD). Although the disorder has an autosomal dominant inheritance pattern, penetrance is reduced in males as opposed to females. Missense, nonsense, splicing, intragenic small deletion/insertion, and gross deletion/duplication pathogenic variants have been reported. Promoter and complete gene deletions have been detected, supporting haploinsufficiency as a likely mechanism for DRD in these cases.

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