ClinGen Dosage Sensitivity Curation Page

DDX3X

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26235985 Snijders et al. report 35 de novo variants in the DDX3X gene in 38 females diagnosed with ID and other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. A wide mutation spectrum was reported, including 5 nonsense variants and 9 frameshift variants. Variants were identified by whole exome sequencing and furthermore, a zebrafish model found a loss-of-function effect on the Wnt pathway of all tested de novo mutations. The authors also describe how in general, pathogenic DDX3X variants in females occur de novo, while males inherit DDX3X missense variants from an unaffected mother; this gender difference may be explained in part because DDX3X is known to escape X-inactivation but it is also suggested that the DDX3X gene is dosage sensitive and may have gender-specific differential activity on the Wnt pathway.
27159028 Fieremans et al. report 2 de novo mutations (one nonsense and one missense) detected by whole exome sequencing in a cohort of 19 females with intellectual disability and skewed X-inactivation.
28327206 Eldomery et al. studied unsolved clinical exome cases. De novo DDX3X mutations were detected by whole exome sequencing in 3 cases with intellectual disability (one frameshift variant and two missense variants).

Haploinsufficiency phenotype comments:

Haploinsufficiency of the DDX3X gene causes X-linked intellectual disability.

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:

No duplications involving only the entire HMBS gene reported

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.