ClinGen Dosage Sensitivity Curation Page

GDI1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9620768 D'Adamo et al. (1998) describe a nonsense mutation, R70X, segregating with disease in a family of seven males with moderate-to-severe intellectual disability (throughout three generations) and two more mildly affected females. The family is described in detail in PMID:9106537. R70X was not found in 100 chromosomes analyzed from individuals amongst different ethnic groups. Lymphoblasts from affected family members did not have any band corresponding to GDI by immunoblotting with anti-GDI antibodies.
22002931 Strobl-Wildemann et al. (2011) published a clinical report on a large family with X-linked intellectual disability and a frameshift variant (NM_001493) (c.1185_1186delAG; Ser396ProfsX15) in GDI1. There are 9 affected males reported in this family, of whom 7 were available for testing. The variant was found in all 7 of these individuals, as well as 2 obligate female carriers and 1 additional female family member said to have a learning disability. No additional studies were performed.

Haploinsufficiency phenotype comments:

Additional missense mutations within GDI1 have been reported cosegregating with intellectual disability including PMID: 28863211, 9668174,9620768 (MRX41) Of note, a Gdi1 knockout mouse has been shown to display a developmental brain disorder phenotype (see PMIDs 12354782, 18829665, 22291894, 26971292 etc.)

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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

Triplosensitivity phenotype comment:

Though duplications within GDI1 ALONE have not been reported, the gene is included within a 0.3 Mb recurrent, variable copy number gain that has been reported in 3 unrelated XLMR families and 1 sporadic case (Vandewalle et al. 2009 PMID 20004760). Additional publications PMID 29341460, 18047645,17546640) See the link for the region elsewhere on this page for further information.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.