Department 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, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
J Med Genet. 2023 Aug;60(8):776-783. doi: 10.1136/jmg-2022-108865. Epub 2022 Dec 12.
gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship between variants and epilepsy.
Whole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases with variants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship between variants and epilepsy.
Four pairs of compound heterozygous variants and one cosegregating heterozygous missense variant in were identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association between variants and epilepsy.
The gene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.
基因编码 Bassoon，这是一种在神经递质释放的活性区组装细胞基质的必需蛋白。本研究旨在探索变体与癫痫之间的关系。
对 313 例（三联体）原因不明癫痫患者进行全外显子组测序。从中国癫痫基因 V.1.0 匹配平台收集更多携带变体的病例。使用 ClinGen 的临床有效性框架来评估变体与癫痫之间的关系。
在五个无关家庭中发现了四个复合杂合变体对和一个共分离杂合错义变体。这些变体在病例队列中的出现频率明显高于对照组。在基因匹配平台的三个无关病例中还发现了另外两个新生杂合无义变体和一个共分离杂合错义变体，它们不存在于基因组聚集数据库中。错义变体倾向于位于 C 末端，包括两个单等位基因错义变体。蛋白质建模表明，在每对复合杂合变体中的至少一个错义变体都有氢键改变。临床上，两个病例被诊断为特发性全面性癫痫，两个为局灶性癫痫，其余四个为热性惊厥附加型癫痫。八个先证者中有七个在婴儿期或儿童期发病。十个受影响的个体中有八个有热性惊厥病史。所有病例均无癫痫发作。携带单等位基因变体的病例在无治疗或单一药物治疗下癫痫无发作，而携带双等位基因错义变体的病例大多需要联合治疗。ClinGen 框架中的证据表明变体与癫痫之间存在关联。
基因可能是癫痫的一个新候选基因。表型严重程度与基因型和变体的分子亚区效应相关。
