ClinGen Dosage Sensitivity Curation Page

KIAA2022

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
2756881 Van Maldergem et al. (2013), studied 8 male patients (4 families) with X-linked intellectual disability and likely pathogenic mutations in the KIAA2022 gene. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array-CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. All patients presented moderate-to-severe ID with autistic features and strabismus. Morphometric studies in cultured rat hippocampal neurons showed that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.
27358180 De Lange et al. (2016), reports 14 female carriers of a heterozygous de novo KIAA2022 mutation. A wide mutation spectrum was reported, including 6 nonesense, 6 small dels, 1 gross del and 1 small insertion. All mutations were LoF, predicted to result in a frameshift or premature stop. The patients presented a neurodevelopmental disorder characterized by intellectual disability and epilepsy. X-inactivation was found to be random in 6 patients, while one patient showed complete skewing.
27568816 Using whole-exome sequencing, Webster et al. (2016), studied 2323 females referred for developmental delay/ID. They identified a cohort of five unrelated females with de novo predicted pathogenic variants in KIAA2022. A wide mutation spectrum was reported, including 2 nonsense,1 frameshift, 1 small del and 1 small dup. All variants were confirmed by Sanger sequencing. The core phenotypic features included ID, developmental delay, impaired language and epilepsy refractory to Treatment.

Haploinsufficiency phenotype comments:

In males, pathogenic variants in KIAA2022 cause a moderate to severe X-linked intellectual disability syndrome that is often associated with strabismus, hypotonia, microcephaly, postnatal growth retardation, motor delay, dysmorphic features, autistic behaviors and seizures (Van Maldergem et al., 2013). Females exhibit a broad phenotypic spectrum. Heterozygous female carriers of inherited variants have been reported to be unaffected (Van Maldergem et al., 2013; Charzewska et al., 2015), while females with de novo loss-of-function variants in KIAA2022 present a phenotype with a less severe intellectual disability compared to hemizygous males, but is more often associated with severe and intractable myoclonic epilepsy (de Lange et al., 2016; Webster et al., 2017). Note: This gene is also known as NEXMIF.

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:

Of note: Charzewska et al., 2015, studied a cohort of 134 Polish patients with X-linked intellectual disability. A duplication of Xq13.3 (chrX:73,899,064-74,262,928; hg19) was reported by array-CGH in 1 family with affected with X-linked intellectual disability. 5 affected males over two generations were identified, and obligatory female carriers were unaffected. The duplication contained the entire KIAA2022 gene with large intergenic flanks of 118 kb and 54 kb pre-ceding and succeeding the gene. The variant co-segregated with ID phenotype in the family. By functional studies, the level of KIAA2022 mRNA was measured in patient?s lymphocytes as well as fibroblasts, showing that the duplication reduced the KIAA2022 expression level in patient?s lymphocytes by 66% and inhibited the expression in patient?s fibroblasts (96%). (PMID: 25394356)

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.