ClinGen Dosage Sensitivity Curation Page

Xq28 recurrent region (includes GDI1)

  • Curation Status: Complete
  • id: ISCA-37439
  • Date last evaluated: 2016-05-26
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

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

Haploinsufficiency phenotype comments:

No published descriptions of reciprocal deletions of this full region yet, although deletions involving FLNA, TAZ and other genes individually are known.

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.

Evidence for triplosensitivity phenotype
PubMed ID Description
20004760 Vandelwalle et al. report an approximate 0.3Mb recurrent, variable copy-number gain region within Xq28 segregating with disease amongst 4 unrelated X-linked intellectual disability families. Though there are 18 annotated genes in the region, GDI1 is proposed by these authors to be the most likely candidate gene, as the copy number of GDI1 appears to correlate with severity. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. The copy number gain was not found in 138 X chromosomes from controls.
17546640 Froyen et al, 2008: A 0.3 Mb duplication of Xq28 including GDI1 was found to segregate with disease (intellectual disability and mild ataxia) within a family of three affected individuals.
18047645 Madrigal et al, 2007: A 250-kb duplication including GDI1, FLNA and EMD genes (but not MECP2) was identified in a male proband, two affected male relatives and two carrier females. The proband exhibited mild intellectual disability, neonatal seizures, motor delay, microcephaly, hyperkinesias and mild dysmorphic features. RT-PCR studies revealed a significantly higher GDI1 expression in the proband and his affected uncle compared to four male controls. The carrier mother showed preferential and complete inactivation of the X-chromosome inherited by the proband (i.e., carrying the 250-kb duplication).

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.