The PAK3 gene has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 07/26/2018 . This association was made using case-level and experimental data. At least 10 variants (missense, nonsense, frameshift and a large deletion) have been reported in humans. PAK3 was first associated with this disease in humans as early as 1998 (Allen et al.). Summary of Case Level Data: 11.2 points. Association is seen in at least 10 probands in 10 publications (9731525, 10946356, 12884430, 17853471, 18523455, 24556213, 25666757, 27753653, 28481730, 28126652). Variants in this gene segregated with disease in 33 additional family members. This gene-disease association is supported by expression studies, in vitro functional assays and animal models. In summary, PAK3 is definitively associated with X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autism and Intellectual Disability Working Group on 7/31/2018.
PAK3 was first reported in relation to X-linked non-syndromic intellectual disability in 1998 (Allen et al., PMID: 9731525) and was subsequently reported in individuals with intellectual disability and syndromic features, including variable dysmorphic features and brain abnormalities. PAK3 encodes a serine/threonine protein kinase that acts as a downstream effector of the small GTPases CDC42 and RAC1. PAK3 plays a role in dendritic spine morphogenesis, synapse formation and plasticity.
Ten variants (missense, nonsense, frameshift and a large deletion) that have been reported in 10 probands in 10 publications (PMIDs: 9731525, 10946356, 12884430, 17853471, 18523455, 24556213, 25666757, 27753653, 28481730, 28126652) are included in this curation. Variants in this gene segregated with disease in 33 additional family members. This gene-disease relationship is also supported by in vitro functional assays and animal models.
In summary, there is definitive evidence supporting the relationship between PAK3 and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autism and Intellectual Disability Gene Curation Expert Panel on July 31, 2018 (SOP Version 5).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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