ClinGen Dosage Sensitivity Curation Page

WDR45

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23435086 Saitsu et al., (2013) identified five patients that had Static encephalopathy of childhood with neurodegeneration in adulthood (SEDNA). As children, the patients in this study were found to have psychomotor development delay and intellectual disability. During adulthood, these patients also presented with cognitive decline, dystonia, parkinsonism, progressive dementia, and four of the patients became bedridden a few years after the initiation of their cognitive decline. Furthermore, cranial magnetic resonance imaging (MRI), revealed that each patient in this study had cerebral and cerebellar atrophy, as well as abnormal iron deposition in the globus pallidus and substantia nigra. Sequence analysis demonstrated that each patient carried a WDR45 mutant allele, with one patient having an in-frame insertion, three patients having insertions that resulted in a premature stop codon, and one patient having a WDR45 nonsense mutation. In vitro expression analysis using lymphoblastoid cell lines derived from each patient revealed that WDR45 protein levels were decreased in the SEDNA patients, when compared to controls. The inheritance pattern of WDR45 mutant alleles was not examined in all cases; however, when inheritance was examined, the mutant alleles were found to be de novo.
23687123 Hayflick et al., (2013) examined 23 patients that were heterozygous for WDR45 mutations. As children, all of the patients in this study presented with developmental delay and intellectual disability, while some of the patients also presented with spasticity, seizures, and disordered sleep. During early adulthood, each patient was found to present with cognitive decline, dystonia, and parkinsonism. Furthermore, cranial magnetic resonance imaging (MRI) revealed that each patient had abnormal iron deposition in the globus pallidus and substantia nigra, while some of the patients also had cerebral and/or cerebellar atrophy. Sequence analysis demonstrated that each patient in this study carried a single WDR45 mutation including several novel missense, nonsense, splice-site, and frameshift mutations. The inheritance pattern of WDR45 mutant alleles was not examined in all cases; however, when inheritance was examined, the mutant alleles were found to be de novo. The alleles identified in this study were proposed to be deleterious and act through a loss-of-function mechanism; however, no functional/expression studies were performed on the mutant alleles.
25044655 Ozawa et al., (2014) identified a single patient who presented with febrile seizures and psychomotor developmental delay during childhood. As an adult, the patient presented with intellectual deterioration, dysphagia, dystonia, spasticity of the limbs, and by the age of 39 she was bedridden and unable to communicate. Cranial magnetic resonance imaging (MRI) revealed cerebral atrophy and iron deposition in the globus pallidus and substantia nigra. Sequence analysis of WDR45 identified a novel frameshift mutation in the proband, which results in the formation of a premature stop codon. This mutation was not found in either of the parents. Functional/expression studies were not performed on the mutant allele.

Haploinsufficiency phenotype comments:

Current evidence includes over 30 patients who are heterozygous carriers of WDR45 mutations (frameshift, nonsense, splice-site, and missense) and present with the neurodegenerative disorder: Static encephalopathy of childhood with neurodegeneration in adulthood (SEDNA) (OMIM#:300894) (PMID: 25044655, 23687123, 23435086, 25263061, 25592411). As children, the patients in these studies presented with developmental delay and intellectual disability. As adults, each patient also presented with intellectual deterioration, iron accumulation in the globus pallidus and substantia nigra, and dystonia. Additional common phenotypes that were described in these SEDNA patients include parkinsonism, atrophy of the brain, dementia, disordered sleep, spasticity, communication problems, and seizures; however, these phenotypes were not described in all patients. It should be noted that, although there are several reported WDR45 nonsense and frameshift mutations, there are currently no reported WDR45 whole gene deletions. It may also be noted that the majority of patients are female, suggesting that loss of function of this gene is male lethal. Affected males are thought to be the result of somatic mosaicism.

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

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.