Abstract
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.
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Acknowledgements
We thank the family and physicians for participation in our study. We are grateful to the He Shanheng Charity Foundation for contributing to the development of this institute.
Funding
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81571273, 81501124, and 81571274), Omics-based Precision Medicine of Epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China (Grant No. 2016YFC0904400), and Science and Technology Project of Guangzhou (Grant Nos. 201,508,020,011, 201,604,020,161, and 201,607,010,002).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Wang, JY., Zhou, P., Wang, J. et al. ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation. Neurogenetics 19, 9–16 (2018). https://doi.org/10.1007/s10048-017-0528-2
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DOI: https://doi.org/10.1007/s10048-017-0528-2