RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis
ABSTRACT Background Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of brain disorders. Variants in the Rho‐related BTB domain‐containing 2 gene (RHOBTB2) can lead to DEE64, which is characterized by early‐onset epilepsy, varying degrees of motor developmental delay and...
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Wiley
2025-01-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.70059 |
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| author | Qian Liu Feifei Li Qin Ruan Nana Wang Zhengjun Fan |
| author_facet | Qian Liu Feifei Li Qin Ruan Nana Wang Zhengjun Fan |
| author_sort | Qian Liu |
| collection | DOAJ |
| description | ABSTRACT Background Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of brain disorders. Variants in the Rho‐related BTB domain‐containing 2 gene (RHOBTB2) can lead to DEE64, which is characterized by early‐onset epilepsy, varying degrees of motor developmental delay and intellectual disability, microcephaly, and movement disorders. More than half of the variants are located at Arg483 and Arg511 within the BTB domain; however, the underlying mechanism of action of these hotspot variants remains unexplored. Methods We performed whole‐exome and Sanger sequencing on the patient and his parents. We collected recurrent variant information from the literature on RHOBTB2 variants. We used Discovery Studio software to analyze the folding free energy of variant proteins, and the AlphaFold database to analyze structural alterations in mutant proteins. Results The patient presented with early‐onset epilepsy, developmental delay, and brain structural abnormalities. Genetic analysis revealed a de novo variant in RHOBTB2, c.1532G>A, p.(Arg511Gln). To date, 60 cases of DEE patients with RHOBTB2 variants have been reported, with approximately 50% of variants located at Arg483 and Arg511. Among them, p.Arg511Gln, p.Arg483His, and p.Arg511Trp have an incidence rate exceeding 10%. The folding free energy of these high‐frequency variants proteins is reduced, which may lead to increased structural stability. Conclusion This study highlights the importance of RHOBTB2 hotspot variants in DEE64 and provides insights into their potential mechanisms of action. We recommend RHOBTB2 gene testing for patients with relevant clinical manifestations to facilitate precise diagnosis and treatment of DEE. |
| format | Article |
| id | doaj-art-a237a6d3286d4fc5a992fa7da26316a6 |
| institution | Kabale University |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-a237a6d3286d4fc5a992fa7da26316a62025-01-24T08:16:42ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-01-01131n/an/a10.1002/mgg3.70059RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant AnalysisQian Liu0Feifei Li1Qin Ruan2Nana Wang3Zhengjun Fan4Department of Pediatrics Taihe County People's Hospital Fuyang Anhui ChinaDepartment of Pediatrics Taihe County People's Hospital Fuyang Anhui ChinaDepartment of Pediatrics Taihe County People's Hospital Fuyang Anhui ChinaDepartment of Pediatrics Taihe County People's Hospital Fuyang Anhui ChinaDepartment of Pediatrics Taihe County People's Hospital Fuyang Anhui ChinaABSTRACT Background Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of brain disorders. Variants in the Rho‐related BTB domain‐containing 2 gene (RHOBTB2) can lead to DEE64, which is characterized by early‐onset epilepsy, varying degrees of motor developmental delay and intellectual disability, microcephaly, and movement disorders. More than half of the variants are located at Arg483 and Arg511 within the BTB domain; however, the underlying mechanism of action of these hotspot variants remains unexplored. Methods We performed whole‐exome and Sanger sequencing on the patient and his parents. We collected recurrent variant information from the literature on RHOBTB2 variants. We used Discovery Studio software to analyze the folding free energy of variant proteins, and the AlphaFold database to analyze structural alterations in mutant proteins. Results The patient presented with early‐onset epilepsy, developmental delay, and brain structural abnormalities. Genetic analysis revealed a de novo variant in RHOBTB2, c.1532G>A, p.(Arg511Gln). To date, 60 cases of DEE patients with RHOBTB2 variants have been reported, with approximately 50% of variants located at Arg483 and Arg511. Among them, p.Arg511Gln, p.Arg483His, and p.Arg511Trp have an incidence rate exceeding 10%. The folding free energy of these high‐frequency variants proteins is reduced, which may lead to increased structural stability. Conclusion This study highlights the importance of RHOBTB2 hotspot variants in DEE64 and provides insights into their potential mechanisms of action. We recommend RHOBTB2 gene testing for patients with relevant clinical manifestations to facilitate precise diagnosis and treatment of DEE.https://doi.org/10.1002/mgg3.70059DEE64developmental and epileptic encephalopathieshotspot variantRHOBTB2 |
| spellingShingle | Qian Liu Feifei Li Qin Ruan Nana Wang Zhengjun Fan RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis Molecular Genetics & Genomic Medicine DEE64 developmental and epileptic encephalopathies hotspot variant RHOBTB2 |
| title | RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis |
| title_full | RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis |
| title_fullStr | RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis |
| title_full_unstemmed | RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis |
| title_short | RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis |
| title_sort | rhobtb2 variant p arg511gln causes developmental and epileptic encephalopathy type 64 in an infant a case report and hotspot variant analysis |
| topic | DEE64 developmental and epileptic encephalopathies hotspot variant RHOBTB2 |
| url | https://doi.org/10.1002/mgg3.70059 |
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