Zhou Peng, Meng Heng, Liang Xiaoyu, Lei Xiaoyun, Zhang Jingwen, Bian Wenjun, He Na, Lin Zhijian, Song Xingwang, Zhu Weiwen, Hu Bin, Li Bingmei, Yan Limin, Tang Bin, Su Tao, Liu Hankui, Mao Yong, Zhai Qiongxiang, Yi Yonghong
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Neurology, The First Affiliated Hospital of Jinan University, Clinical Neuroscience Institute of Jinan University, Guangzhou, China.
Front Mol Neurosci. 2022 Jun 23;15:864074. doi: 10.3389/fnmol.2022.864074. eCollection 2022.
gene encodes adhesion G protein-coupled receptor-V1 that is involved in synaptic function. mutations are associated with audio-visual disorders. Although previous experimental studies suggested that variants were associated with epilepsy, clinical evidence is limited and the phenotype spectrum is to be defined.
Trio-based targeting sequencing was performed in a cohort of 101 cases with febrile seizure (FS) and epilepsy with antecedent FS. Protein modeling was used to assess the damaging effects of variants. The genotype-phenotype correlations of the variants in epilepsy and audio-visual disorders were analyzed.
variants were identified in nine unrelated cases (8.91%), including two heterozygous frameshift variants, six heterozygous missense variants, and a pair of compound heterozygous variants. These variants presented a statistically higher frequency in this cohort than that in control populations. Most missense variants were located at CalX-β motifs and changed the hydrogen bonds. These variants were inherited from the asymptomatic parents, indicating an incomplete penetrance. We also identified variants in 25 unrelated cases (24.75%) and variants in 3 unrelated cases (2.97%) in this cohort. Contrary to variant-associated epilepsy that revealed seizure was aggravated by sodium channel blockers, variants were associated with mild epilepsy with favorable responses to antiepileptic drugs. The patients denied problems with audio-visual-vestibular abilities in daily life. However, audio-visual tests revealed auditory and visual impairment in the patient with compound heterozygous variants, auditory or vestibular impairment in the patients with heterozygous frameshift, or hydrogen-bond changed missense variants but no abnormalities in the patients with missense variants without hydrogen-bond changes. Previously reported variants that were associated with audio-visual disorders were mostly biallelic/destructive variants, which were significantly more frequent in the severe phenotype of audio-visual disorders (Usher syndrome 2) than in other mild phenotypes. In contrast, the variants identified in epilepsy were monoallelic, missense mainly located at CalX-β, or affected isoforms VLGR1b/1c.
is potentially associated with FS-related epilepsy as a susceptibility gene. The genotype, submolecular implication, isoforms, and damaging severity of the variants explained the phenotypical variations. variant-associated FS/epilepsy presented favorable responses to antiepileptic drugs, implying a clinical significance.
基因编码参与突触功能的粘附G蛋白偶联受体-V1。突变与视听障碍有关。尽管先前的实验研究表明变体与癫痫有关，但临床证据有限，且表型谱有待确定。
对101例热性惊厥（FS）和有FS病史的癫痫患者进行基于三联体的靶向测序。使用蛋白质建模来评估变体的有害影响。分析了癫痫和视听障碍中变体的基因型-表型相关性。
在9例无关病例（8.91%）中鉴定出变体，包括2个杂合移码变体、6个杂合错义变体和一对复合杂合变体。这些变体在该队列中的频率在统计学上高于对照人群。大多数错义变体位于CalX-β基序处并改变了氢键。这些变体是从无症状的父母遗传而来，表明存在不完全外显率。在该队列中，我们还在25例无关病例（24.75%）中鉴定出变体，在3例无关病例（2.97%）中鉴定出变体。与显示钠通道阻滞剂会加重发作的变体相关癫痫相反，变体与对抗癫痫药物反应良好的轻度癫痫有关。患者在日常生活中否认有视听-前庭能力问题。然而，视听测试显示，复合杂合变体患者存在听觉和视觉障碍，杂合移码或氢键改变的错义变体患者存在听觉或前庭障碍，但无氢键改变的错义变体患者无异常。先前报道的与视听障碍相关的变体大多是双等位基因/破坏性变体，在严重的视听障碍表型（Usher综合征2型）中比在其他轻度表型中更频繁。相比之下，在癫痫中鉴定出的变体是单等位基因，错义主要位于CalX-β，或影响亚型VLGR1b/1c。
作为一个易感基因，可能与FS相关癫痫有关。变体的基因型、亚分子影响、亚型和有害严重程度解释了表型变异。变体相关的FS/癫痫对抗癫痫药物反应良好，具有临床意义。
