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Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders

STXBP1 variants are one of the most common genetic causes of neurodevelopmental disorders and epilepsy, wherein STXBP1-related disorders are characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of affected patients. However, the spectrums of both genotype and phenotype are qu...

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Autores principales: Wang, Haiping, Chen, Xiuli, Liu, Zhanli, Chen, Chen, Liu, Xin, Huang, Mingwei, Zhou, Zhuying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086123/
https://www.ncbi.nlm.nih.gov/pubmed/37056358
http://dx.doi.org/10.3389/fneur.2023.1146875
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author Wang, Haiping
Chen, Xiuli
Liu, Zhanli
Chen, Chen
Liu, Xin
Huang, Mingwei
Zhou, Zhuying
author_facet Wang, Haiping
Chen, Xiuli
Liu, Zhanli
Chen, Chen
Liu, Xin
Huang, Mingwei
Zhou, Zhuying
author_sort Wang, Haiping
collection PubMed
description STXBP1 variants are one of the most common genetic causes of neurodevelopmental disorders and epilepsy, wherein STXBP1-related disorders are characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of affected patients. However, the spectrums of both genotype and phenotype are quite wide and diverse, with a high baseline variability even for recurrent STXBP1 variants. Until now, no clear genotype–phenotype correlations have been established and multiple disease mechanisms have been proposed for STXBP1-related disorders. Without an ascertained disease cause for many cases of STXBP1 variants, it is challenging to manage this disease in an effective manner and current symptom-based treatments are focused on seizure control only, which has a minimal impact on global development. A novel STXBP1 canonical splice variant, NM_001032221.4:c.578+2T>C, was reported in this study, together with detailed documentation of disease manifestations and treatment management. Further RNA expression analysis revealed abnormal intron retention and possible production of truncated STXBP1 proteins as a likely pathogenic mechanism. More importantly, the landscape of previously understudied STXBP1 splice variants and functional investigations was assessed for the first time to provide a context for the discussion of the complicated genotype–phenotype relationship of STXBP1-related disorders. Future cases of this disorder and a deeper mechanism-based understanding of its pathogenic cause are required for precision medicine and better disease management.
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spelling pubmed-100861232023-04-12 Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders Wang, Haiping Chen, Xiuli Liu, Zhanli Chen, Chen Liu, Xin Huang, Mingwei Zhou, Zhuying Front Neurol Neurology STXBP1 variants are one of the most common genetic causes of neurodevelopmental disorders and epilepsy, wherein STXBP1-related disorders are characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of affected patients. However, the spectrums of both genotype and phenotype are quite wide and diverse, with a high baseline variability even for recurrent STXBP1 variants. Until now, no clear genotype–phenotype correlations have been established and multiple disease mechanisms have been proposed for STXBP1-related disorders. Without an ascertained disease cause for many cases of STXBP1 variants, it is challenging to manage this disease in an effective manner and current symptom-based treatments are focused on seizure control only, which has a minimal impact on global development. A novel STXBP1 canonical splice variant, NM_001032221.4:c.578+2T>C, was reported in this study, together with detailed documentation of disease manifestations and treatment management. Further RNA expression analysis revealed abnormal intron retention and possible production of truncated STXBP1 proteins as a likely pathogenic mechanism. More importantly, the landscape of previously understudied STXBP1 splice variants and functional investigations was assessed for the first time to provide a context for the discussion of the complicated genotype–phenotype relationship of STXBP1-related disorders. Future cases of this disorder and a deeper mechanism-based understanding of its pathogenic cause are required for precision medicine and better disease management. Frontiers Media S.A. 2023-03-28 /pmc/articles/PMC10086123/ /pubmed/37056358 http://dx.doi.org/10.3389/fneur.2023.1146875 Text en Copyright © 2023 Wang, Chen, Liu, Chen, Liu, Huang and Zhou. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Wang, Haiping
Chen, Xiuli
Liu, Zhanli
Chen, Chen
Liu, Xin
Huang, Mingwei
Zhou, Zhuying
Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title_full Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title_fullStr Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title_full_unstemmed Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title_short Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1-related disorders
title_sort case report: a novel stxbp1 splice variant and the landscape of splicing-involved stxbp1-related disorders
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086123/
https://www.ncbi.nlm.nih.gov/pubmed/37056358
http://dx.doi.org/10.3389/fneur.2023.1146875
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