ClinGen Dosage Sensitivity Curation Page

PAK3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
18523455 Rejeb et al (2008): A report of a family with X-linked intellectual disability with a splice variant (c.276+4A>G). The variant resulted in complete loss of normal transcript and created a transcript with four additional nucleotides that ultimately led to a premature stop codon. Carrier females were phenotypically normal and had skewed X-inactivation. At least five segregations are observed in this family, not counting the branch of the family that was not formally tested.
9731525 Allen et al (1998): A report of a family with X-linked intellectual disability with a nonsense variant. The resulting protein lacks kinase activity. All carrier females were phenotypically normal; X-inactivation studies were not done.
27753653 Cartwright et al (2017) identified an assumed de novo deletion on chromosomal microarray involving exons 4-15 of the 3 prime end of the PAK3 gene in a male with autism spectrum disorder, intellectual disability, and dysmorphic features.

Haploinsufficiency phenotype comments:

In addition to the variants listed above, several missense variants have been reported in families with X-linked intellectual disability, one of which includes affected females (PMIDs: 17853471, 12884430 and 10946356). Functional studies show that some of these missense variants result in loss-of-function (PMID 24556213). In addition, Meng et al (2005) (PMID 16014725) used a knock-out mouse model to show abnormalities in synaptic plasticity and deficiencies in learning and memory. Hoischen et al (2009) also report a female with intellectual disability and nephropathy who had a microdeletion that includes PAK3 as well as other genes such as DCX and COL4A5.

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.