Intellectual Disability via the PAK3 Gene

X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) in males. Mental Retardation, X-linked 30 (MRX30) is a condition of non-syndromic XLID that mostly affects males, although carrier females exhibit occasional symptoms (Peippo et al. 2007). The affected individuals display borderline to severe intellectual disability, with sporadic involvement of additional features such as dysmorphic faces with large ears, upslanting palpebral fissures, oromotor impairment (like drooling, speech difficulties), microcephaly, agenesis of corpus callosum, cerebellar hypoplasia, hypotonia, paranoid psychosis, epilepsy, anxiety, aggression, and schizophrenia (Gedeon et al. 2003; Peippo et al. 2007; Rejeb et al. 2008).

Pathogenic variants in PAK3 have been reported in multiple families with MRX30. PAK3 gene maps to Xq21.3-q24 and consists of 18 exons that encode a 544 amino acid polypeptide. PAK3 serine/threonine kinase forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1, which is necessary for dendrite spine morphogenesis as well as synapse formation and plasticity (Boda et al. 2008, Manser et al. 1994, Huang et al. 2011). Loss-of-function variants in p21-activated kinase-3 gene (PAK3) abolish the kinase activity of the PAK3 protein and contribute to MRX30 by affecting the dendritic spine density and morphology via MAPK signaling (Magini et al. 2014). Nonsense, missense and splicing variants have been reported in PAK3. The disease transmission pattern is X-linked recessive.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 100 genes have been identified in individuals with XLID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016). Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

To date, there is no report of any large deletion or duplication involving this gene.

This test provides full coverage of all coding exons of the PAK3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).