De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis
BackgroundEpilepsy with febrile seizures plus (EFS+) is a syndrome with a strong genetic component. Previously, variants in several genes encoding ion channels have been associated with EFS+. However, the etiology in the majority of patients remains undetermined.MethodsTrio-based whole-exome sequenc...
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Frontiers Media S.A.
2025-03-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1499716/full |
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| author | Hong-Jun Yan Wen-Hui Liu Min-Xing Xu Peng-Yu Wang Yu-Jie Gu Hua Li Jing Guo Sheng Luo |
| author_facet | Hong-Jun Yan Wen-Hui Liu Min-Xing Xu Peng-Yu Wang Yu-Jie Gu Hua Li Jing Guo Sheng Luo |
| author_sort | Hong-Jun Yan |
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| description | BackgroundEpilepsy with febrile seizures plus (EFS+) is a syndrome with a strong genetic component. Previously, variants in several genes encoding ion channels have been associated with EFS+. However, the etiology in the majority of patients remains undetermined.MethodsTrio-based whole-exome sequencing was performed on a patient with EFS+. Previously reported KCNK4 variants were systemically reviewed to analyze the phenotypic spectrum and core phenotypes.ResultsA novel de novo KCNK4 variant (c.415G>A/p.Gly139Arg) was identified in a patient with EFS+, neurodevelopmental abnormalities, and hypertrichosis. The identified variant was absent in normal populations, indicated to alter hydrogen bonds with surrounding residues by various protein modeling, predicted to be damaging for protein function by twenty algorithms, located in residues of high conservation across species, and classified as pathogenic by the ACMG guidelines. Protein modeling analyses of the variant suggested a possible gain-of-function effect. Analysis of other eight cases with KCNK4 variants outlined the phenotypic spectrums of KCNK4, ranging from mild benign epilepsy, EFS+ with neurodevelopmental abnormalities, to syndromic neurodevelopmental disorders and revealed neurodevelopmental abnormalities and epilepsy as its core phenotypes. Integrated analysis suggested that minor allele frequency and in silico meta-predictors effectively distinguish pathogenic variants.ConclusionThis study suggested the KCNK4 gene as a novel candidate causative gene of EFS+, which would be helpful for the genetic diagnosis and clinical management of patients. |
| format | Article |
| id | doaj-art-270f00fbfc404cc48a5b4fc2c44dedd8 |
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| language | English |
| publishDate | 2025-03-01 |
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| series | Frontiers in Genetics |
| spelling | doaj-art-270f00fbfc404cc48a5b4fc2c44dedd82025-08-20T02:10:50ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-03-011610.3389/fgene.2025.14997161499716De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosisHong-Jun Yan0Wen-Hui Liu1Min-Xing Xu2Peng-Yu Wang3Yu-Jie Gu4Hua Li5Jing Guo6Sheng Luo7Epilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong, ChinaInstitute 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, Guangdong, ChinaDepartment of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaInstitute 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, Guangdong, ChinaInstitute 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, Guangdong, ChinaEpilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong, ChinaEpilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong, ChinaInstitute 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, Guangdong, ChinaBackgroundEpilepsy with febrile seizures plus (EFS+) is a syndrome with a strong genetic component. Previously, variants in several genes encoding ion channels have been associated with EFS+. However, the etiology in the majority of patients remains undetermined.MethodsTrio-based whole-exome sequencing was performed on a patient with EFS+. Previously reported KCNK4 variants were systemically reviewed to analyze the phenotypic spectrum and core phenotypes.ResultsA novel de novo KCNK4 variant (c.415G>A/p.Gly139Arg) was identified in a patient with EFS+, neurodevelopmental abnormalities, and hypertrichosis. The identified variant was absent in normal populations, indicated to alter hydrogen bonds with surrounding residues by various protein modeling, predicted to be damaging for protein function by twenty algorithms, located in residues of high conservation across species, and classified as pathogenic by the ACMG guidelines. Protein modeling analyses of the variant suggested a possible gain-of-function effect. Analysis of other eight cases with KCNK4 variants outlined the phenotypic spectrums of KCNK4, ranging from mild benign epilepsy, EFS+ with neurodevelopmental abnormalities, to syndromic neurodevelopmental disorders and revealed neurodevelopmental abnormalities and epilepsy as its core phenotypes. Integrated analysis suggested that minor allele frequency and in silico meta-predictors effectively distinguish pathogenic variants.ConclusionThis study suggested the KCNK4 gene as a novel candidate causative gene of EFS+, which would be helpful for the genetic diagnosis and clinical management of patients.https://www.frontiersin.org/articles/10.3389/fgene.2025.1499716/fullKCNK4epilepsy with febrile seizures plusphenotypic spectrumspatiotemporal expressionphenotypic variation |
| spellingShingle | Hong-Jun Yan Wen-Hui Liu Min-Xing Xu Peng-Yu Wang Yu-Jie Gu Hua Li Jing Guo Sheng Luo De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis Frontiers in Genetics KCNK4 epilepsy with febrile seizures plus phenotypic spectrum spatiotemporal expression phenotypic variation |
| title | De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis |
| title_full | De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis |
| title_fullStr | De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis |
| title_full_unstemmed | De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis |
| title_short | De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis |
| title_sort | de novo kcnk4 variant caused epilepsy with febrile seizures plus neurodevelopmental abnormalities and hypertrichosis |
| topic | KCNK4 epilepsy with febrile seizures plus phenotypic spectrum spatiotemporal expression phenotypic variation |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1499716/full |
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