DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation
BackgroundThe DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, DLG3 has been identified as the causative gene of X-linked intellectual de...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1290919/full |
| _version_ | 1797365613892468736 |
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| author | Yun-Yan He Yun-Yan He Sheng Luo Liang Jin Liang Jin Peng-Yu Wang Jie Xu Hong-Liang Jiao Hong-Jun Yan Yao Wang Qiong-Xiang Zhai Jing-Jing Ji Weng-Jun Zhang Peng Zhou Hua Li Wei-Ping Liao Song Lan Lin Xu |
| author_facet | Yun-Yan He Yun-Yan He Sheng Luo Liang Jin Liang Jin Peng-Yu Wang Jie Xu Hong-Liang Jiao Hong-Jun Yan Yao Wang Qiong-Xiang Zhai Jing-Jing Ji Weng-Jun Zhang Peng Zhou Hua Li Wei-Ping Liao Song Lan Lin Xu |
| author_sort | Yun-Yan He |
| collection | DOAJ |
| description | BackgroundThe DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, DLG3 has been identified as the causative gene of X-linked intellectual developmental disorder—90 (XLID-90; OMIM# 300850). This study aims to explore the phenotypic spectrum of DLG3 and the genotype-phenotype correlation.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy of unknown causes. To analyze the genotype-phenotype correlations, previously reported DLG3 variants were systematically reviewed.ResultsDLG3 variants were identified in seven unrelated cases with epilepsy. These variants had no hemizygous frequencies in controls. All variants were predicted to be damaging by silico tools and alter the hydrogen bonds with surrounding residues and/or protein stability. Four cases mainly presented with generalized seizures, including generalized tonic-clonic and myoclonic seizures, and the other three cases exhibited secondary generalized tonic-clonic seizures and focal seizures. Multifocal discharges were recorded in all cases during electroencephalography monitoring, including the four cases with generalized discharges initially but multifocal discharges after drug treating. Protein-protein interaction network analysis revealed that DLG3 interacts with 52 genes with high confidence, in which the majority of disease-causing genes were associated with a wide spectrum of neurodevelopmental disorder (NDD) and epilepsy. Three patients with variants locating outside functional domains all achieved seizure-free, while the four patients with variants locating in functional domains presented poor control of seizures. Analysis of previously reported cases revealed that patients with non-null variants presented higher percentages of epilepsy than those with null variants, suggesting a genotype-phenotype correlation.SignificanceThis study suggested that DLG3 variants were associated with epilepsy with/without NDD, expanding the phenotypic spectrum of DLG3. The observed genotype-phenotype correlation potentially contributes to the understanding of the underlying mechanisms driving phenotypic variation. |
| first_indexed | 2024-03-08T16:52:24Z |
| format | Article |
| id | doaj.art-d7aafe8f0f10474ebabc753ade012823 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-08T16:52:24Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-d7aafe8f0f10474ebabc753ade0128232024-01-05T04:22:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-01-011610.3389/fnmol.2023.12909191290919DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlationYun-Yan He0Yun-Yan He1Sheng Luo2Liang Jin3Liang Jin4Peng-Yu Wang5Jie Xu6Hong-Liang Jiao7Hong-Jun Yan8Yao Wang9Qiong-Xiang Zhai10Jing-Jing Ji11Weng-Jun Zhang12Peng Zhou13Hua Li14Wei-Ping Liao15Song Lan16Lin Xu17Department of Neurology, Women and Children’s Hospital, Qingdao University, Qingdao, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaEpilepsy Center, Guangdong 999 Brain Hospital, Guangzhou, ChinaEpilepsy Center, Guangdong 999 Brain Hospital, Guangzhou, ChinaDepartment of Pediatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaEpilepsy Center, Guangdong 999 Brain Hospital, Guangzhou, ChinaDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology, Maoming People’s Hospital, Maoming, ChinaDepartment of Neurology, Women and Children’s Hospital, Qingdao University, Qingdao, ChinaBackgroundThe DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, DLG3 has been identified as the causative gene of X-linked intellectual developmental disorder—90 (XLID-90; OMIM# 300850). This study aims to explore the phenotypic spectrum of DLG3 and the genotype-phenotype correlation.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy of unknown causes. To analyze the genotype-phenotype correlations, previously reported DLG3 variants were systematically reviewed.ResultsDLG3 variants were identified in seven unrelated cases with epilepsy. These variants had no hemizygous frequencies in controls. All variants were predicted to be damaging by silico tools and alter the hydrogen bonds with surrounding residues and/or protein stability. Four cases mainly presented with generalized seizures, including generalized tonic-clonic and myoclonic seizures, and the other three cases exhibited secondary generalized tonic-clonic seizures and focal seizures. Multifocal discharges were recorded in all cases during electroencephalography monitoring, including the four cases with generalized discharges initially but multifocal discharges after drug treating. Protein-protein interaction network analysis revealed that DLG3 interacts with 52 genes with high confidence, in which the majority of disease-causing genes were associated with a wide spectrum of neurodevelopmental disorder (NDD) and epilepsy. Three patients with variants locating outside functional domains all achieved seizure-free, while the four patients with variants locating in functional domains presented poor control of seizures. Analysis of previously reported cases revealed that patients with non-null variants presented higher percentages of epilepsy than those with null variants, suggesting a genotype-phenotype correlation.SignificanceThis study suggested that DLG3 variants were associated with epilepsy with/without NDD, expanding the phenotypic spectrum of DLG3. The observed genotype-phenotype correlation potentially contributes to the understanding of the underlying mechanisms driving phenotypic variation.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1290919/fullDLG3 geneepilepsyneurodevelopmental disordervariantsGenotype-phenotype correlation |
| spellingShingle | Yun-Yan He Yun-Yan He Sheng Luo Liang Jin Liang Jin Peng-Yu Wang Jie Xu Hong-Liang Jiao Hong-Jun Yan Yao Wang Qiong-Xiang Zhai Jing-Jing Ji Weng-Jun Zhang Peng Zhou Hua Li Wei-Ping Liao Song Lan Lin Xu DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation Frontiers in Molecular Neuroscience DLG3 gene epilepsy neurodevelopmental disorder variants Genotype-phenotype correlation |
| title | DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation |
| title_full | DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation |
| title_fullStr | DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation |
| title_full_unstemmed | DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation |
| title_short | DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation |
| title_sort | dlg3 variants caused x linked epilepsy with without neurodevelopmental disorders and the genotype phenotype correlation |
| topic | DLG3 gene epilepsy neurodevelopmental disorder variants Genotype-phenotype correlation |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1290919/full |
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