Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy

  • Ruen Yao
  • Yi Zhang
  • Jie Liu
  • Jiwen Wang
  • Yufei Xu
  • Niu Li
  • Jian WangEmail author
  • Tingting YuEmail author


Mutations in the rho guanine nucleotide exchange factor 9 gene (ARHGEF9) are present in patients with heterogeneous phenotypes including psychomotor developmental delay and variable degrees of epilepsy. Malfunction of collybistin (CB) encoded by ARHGEF9 leading to impaired clustering of gephyrin-dependent glycine receptors and γ-aminobutyric acid type A (GABAα) receptors is a crucial pathogenic mechanism. Here, we report on three patients with epilepsy and mental retardation. We studied three male patients with epilepsy and mild to moderate mental retardation. We conducted targeted panel sequencing of genes known to cause inherited disorders. In vitro studies and transcriptional experiments were performed to evaluate the functional and splicing effects of these variants on CB. Two novel missense variants (p.I294T and p.R357I) and one novel splicing variant (c.381+3A>G) in ARHGEF9 were identified in the three patients, respectively. In vitro studies confirmed that the two missense variants disrupted CB-mediated accumulation of gephyrin in submembrane microclusters. Transcriptional experiments of the splicing variant revealed the presence of aberrant transcripts leading to truncated protein product. Significance: Our cases and functional studies enrich our understanding of the phenotypic and genotypic spectrum of ARHGEF9.


Epilepsy ARHGEF9 Missense Splice variant Collybistin 



We thank all the members of the family for their participation in this study.

Funding Information

This study was supported by the National Natural Science Foundation of China (Grant No. 81873984, 181772303), the Project of Shanghai Municipal Science and Technology Commission (Grant No. 16ZR1421700), the young talents training program of Shanghai Municipal Health Commission (Grant No. 2018YQ24), “Shuguang Program” of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (Grant No. 18SG14), and the Project of Shanghai Municipal Education Commission-Gaofeng Clinical Medicine (Grant No. 20152529).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at Shanghai Children’s Medical Center (SCMCIRB-Y2019021) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from the parents of all individual participants included in the study.

Supplementary material

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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical CenterShanghai Jiaotong University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Department of Neurology, Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China

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