A novel PAK3 pathogenic variant identified in two siblings from a Japanese family with X-linked intellectual disability: case report and review of the literature

Abstract

Intellectual disability (ID) is a clinically and genetically heterogeneous developmental brain disorder. The present study describes two male siblings, aged 7 and 1 yr old, with severe ID, spastic quadriplegia, nystagmus, and brain atrophy with acquired microcephaly. We used the exome sequencing to identify the causative gene in the patients and identified a hemizygous missense variant, c.1282T>A (p.W428R), in the p21-activated serine/threonine kinase 3 gene (PAK3), which is associated with X-linked ID. p.W428R is located within the highly conserved kinase domain and was predicted to induce loss of enzymatic function by three mutation prediction tools (SIFT, PolyPhen-2, and MutationTaster). In addition, this variant has not been reported in public databases (as of the middle of December 2018) or in the data from 3275 individuals of the Japanese general population analyzed using high-depth whole-genome sequencing. To date, only 13 point mutations and deletions in PAK3 in ID have been reported. The literature review illustrated a phenotypic spectrum of PAK3 pathogenic variant, and our cases represented the most severe form of the PAK3-associated phenotypes. This is the first report of a PAK3 pathogenic variant in Japanese patients with X-linked ID.

Protein-Activated Kinase 3 (PAK3)-Related Intellectual Disability Associated with Combined Immunodeficiency: A Case Report

“…Our patient, similar to others with a PAK3 mutation, had no history of seizures; however, other families had members with epilepsy, which shows the clinical heterogeneity of PAK3 mutations [ 6 – 8 ].…”

“…The patient had features similar to those reported for other families carrying a PAK3 mutation, and comparisons are made in Table 1 [ 6 – 8 ]. A previous study reporting a multiplex pedigree family with a point mutation in PAK3 suggested that PAK signaling may be critical for neuronal connections underlying human cognitive function [ 4 ].…”

Novel PAK3 gene missense variant associated with two Chinese siblings with intellectual disability: a case report

“…Twelve of them were located in the KD, and two were in the PBD/AID. Currently, only 1 deletion in exon 6-18 has been reported, which covers the major area of the PBD/AID and all of the KD [2,[8][9][10][11][12][13][14][15][16][17][18][19][20] (Table 2, Fig. 2).…”

PAK3 controls the tangential to radial migration switch of cortical interneurons by coordinating changes in cell shape and polarity

“…PAK3 mutations in humans are responsible for ID, developmental delay including motor and speech deficits, behavioral problems linked to increased aggression and violence, and severe epilepsy (Allen et al, 1998; Horvath et al, 2018; Iida et al, 2019; Magini et al, 2014; Rejeb et al, 2008). Behavior abnormalities belonging to the autistic spectrum, aggression, schizophreniform psychosis have been reported in patients with PAK3 mutations (Horvath et al, 2018; Qian et al, 2020).…”