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

Aritoshi Iida, Kyoko Takano, Eri Takeshita, Chihiro Abe-Hatano, Shinichi Hirabayashi, Yuji Inaba, Shunichi Kosugi, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Eiji Nakagawa, Ken Inoue, Yu Ichi Goto

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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 from3275 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.

Original languageEnglish
Article numbera003988
JournalCold Spring Harbor Molecular Case Studies
Volume5
Issue number6
DOIs
Publication statusPublished - 01-01-2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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    Iida, A., Takano, K., Takeshita, E., Abe-Hatano, C., Hirabayashi, S., Inaba, Y., Kosugi, S., Kamatani, Y., Momozawa, Y., Kubo, M., Nakagawa, E., Inoue, K., & Goto, Y. I. (2019). 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. Cold Spring Harbor Molecular Case Studies, 5(6), [a003988]. https://doi.org/10.1101/mcs.a003988