Xiao Li , Hui Sun , Yang Tian , Song Lan , Kaixian Du , Hao Chen , Lin Li , Jing Guan , Qiongxiang Zhai , Jie Wang , Bin Li
{"title":"CDK5RAP2作为局灶性癫痫无小头畸形致病基因的鉴定","authors":"Xiao Li , Hui Sun , Yang Tian , Song Lan , Kaixian Du , Hao Chen , Lin Li , Jing Guan , Qiongxiang Zhai , Jie Wang , Bin Li","doi":"10.1016/j.seizure.2025.08.018","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>The <em>CDK5RAP2</em> gene, which encodes a regulator of cyclin-dependent kinase activity, plays a vital role in brain development. <em>CDK5RAP2</em> variants have been previously reported in patients with primary microcephaly-3, with or without epilepsy. This study aimed to investigate the association between <em>CDK5RAP2</em> and epilepsy.</div></div><div><h3>Method</h3><div>Trio-based whole-exome sequencing was performed in patients with idiopathic focal epilepsy without acquired causes. Sub-regional effects, genotype-phenotype correlation, and protein-protein interactions were analysed to reveal gene-disease association.</div></div><div><h3>Results</h3><div>Four compound heterozygous <em>CDK5RAP2</em> variants were identified in four unrelated cases. These variants had no or extremely low allele frequencies in the controls and showed statistically higher frequencies than those in the controls. These variants were predicted to have changes in hydrogen bonds, decreased protein stability, and significant alterations in the hydrophobicity. All patients had focal epilepsy without microcephaly. Patient in one case with two variants of paired missense variants located at the functional domain showed refractory seizures, whereas another patient with variants outside functional domains was seizure-free, suggesting a potential sub-regional effect. The proportion of missense variants in the epilepsy group was significantly higher than that in the primary microcephaly group, suggesting a potential genotype-phenotype correlation. Protein-protein interaction analysis showed that CDK5RAP2 interacted with 31 proteins with high confidence, of which 13 genes were associated with epilepsy and neurodevelopmental disorders, suggesting a potential association between <em>CDK5RAP2</em> and epilepsy.</div></div><div><h3>Conclusion</h3><div><em>CDK5RAP2</em> is a novel causative gene for focal epilepsy without microcephaly.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"131 ","pages":"Pages 435-442"},"PeriodicalIF":2.8000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of CDK5RAP2 as a causative gene of focal epilepsy without microcephaly\",\"authors\":\"Xiao Li , Hui Sun , Yang Tian , Song Lan , Kaixian Du , Hao Chen , Lin Li , Jing Guan , Qiongxiang Zhai , Jie Wang , Bin Li\",\"doi\":\"10.1016/j.seizure.2025.08.018\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>The <em>CDK5RAP2</em> gene, which encodes a regulator of cyclin-dependent kinase activity, plays a vital role in brain development. <em>CDK5RAP2</em> variants have been previously reported in patients with primary microcephaly-3, with or without epilepsy. This study aimed to investigate the association between <em>CDK5RAP2</em> and epilepsy.</div></div><div><h3>Method</h3><div>Trio-based whole-exome sequencing was performed in patients with idiopathic focal epilepsy without acquired causes. Sub-regional effects, genotype-phenotype correlation, and protein-protein interactions were analysed to reveal gene-disease association.</div></div><div><h3>Results</h3><div>Four compound heterozygous <em>CDK5RAP2</em> variants were identified in four unrelated cases. These variants had no or extremely low allele frequencies in the controls and showed statistically higher frequencies than those in the controls. These variants were predicted to have changes in hydrogen bonds, decreased protein stability, and significant alterations in the hydrophobicity. All patients had focal epilepsy without microcephaly. Patient in one case with two variants of paired missense variants located at the functional domain showed refractory seizures, whereas another patient with variants outside functional domains was seizure-free, suggesting a potential sub-regional effect. The proportion of missense variants in the epilepsy group was significantly higher than that in the primary microcephaly group, suggesting a potential genotype-phenotype correlation. Protein-protein interaction analysis showed that CDK5RAP2 interacted with 31 proteins with high confidence, of which 13 genes were associated with epilepsy and neurodevelopmental disorders, suggesting a potential association between <em>CDK5RAP2</em> and epilepsy.</div></div><div><h3>Conclusion</h3><div><em>CDK5RAP2</em> is a novel causative gene for focal epilepsy without microcephaly.</div></div>\",\"PeriodicalId\":49552,\"journal\":{\"name\":\"Seizure-European Journal of Epilepsy\",\"volume\":\"131 \",\"pages\":\"Pages 435-442\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Seizure-European Journal of Epilepsy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1059131125002134\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seizure-European Journal of Epilepsy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1059131125002134","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Identification of CDK5RAP2 as a causative gene of focal epilepsy without microcephaly
Objective
The CDK5RAP2 gene, which encodes a regulator of cyclin-dependent kinase activity, plays a vital role in brain development. CDK5RAP2 variants have been previously reported in patients with primary microcephaly-3, with or without epilepsy. This study aimed to investigate the association between CDK5RAP2 and epilepsy.
Method
Trio-based whole-exome sequencing was performed in patients with idiopathic focal epilepsy without acquired causes. Sub-regional effects, genotype-phenotype correlation, and protein-protein interactions were analysed to reveal gene-disease association.
Results
Four compound heterozygous CDK5RAP2 variants were identified in four unrelated cases. These variants had no or extremely low allele frequencies in the controls and showed statistically higher frequencies than those in the controls. These variants were predicted to have changes in hydrogen bonds, decreased protein stability, and significant alterations in the hydrophobicity. All patients had focal epilepsy without microcephaly. Patient in one case with two variants of paired missense variants located at the functional domain showed refractory seizures, whereas another patient with variants outside functional domains was seizure-free, suggesting a potential sub-regional effect. The proportion of missense variants in the epilepsy group was significantly higher than that in the primary microcephaly group, suggesting a potential genotype-phenotype correlation. Protein-protein interaction analysis showed that CDK5RAP2 interacted with 31 proteins with high confidence, of which 13 genes were associated with epilepsy and neurodevelopmental disorders, suggesting a potential association between CDK5RAP2 and epilepsy.
Conclusion
CDK5RAP2 is a novel causative gene for focal epilepsy without microcephaly.
期刊介绍:
Seizure - European Journal of Epilepsy is an international journal owned by Epilepsy Action (the largest member led epilepsy organisation in the UK). It provides a forum for papers on all topics related to epilepsy and seizure disorders.