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Abstract：
EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants.
We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and \"microdysgenesis\" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants.
Nine variants were classified as \"pathogenic,\" 14 as \"likely pathogenic,\" 9 as \"benign,\" and 2 as \"likely benign.\" Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls.
NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and \"microdysgenesis\" neuropathology of JME.Genet Med 19 2, 144-156.
We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and \"microdysgenesis\" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants.
Nine variants were classified as \"pathogenic,\" 14 as \"likely pathogenic,\" 9 as \"benign,\" and 2 as \"likely benign.\" Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls.
NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and \"microdysgenesis\" neuropathology of JME.Genet Med 19 2, 144-156.
摘要：
EFHC1变体是青少年肌阵挛性癫痫（JME）的遗传性肌阵挛性和大阵挛性-强直-阵挛性（CTC）惊厥中最常见的突变。我们根据国家人类基因组研究研究所（NHGRI）和美国医学遗传学和基因组学学院（ACMG）的序列变异解释指南，重新分析了17个队列中与癫痫相关的54种EFHC1变异。
我们计算了共同继承中变体的贝叶斯LOD分数，病例对照关联中的无条件精确测试和优势比(OR)，基因组数据库中的等位基因频率，以及保守性/致病性的预测。我们回顾了变体是否会损害EFHC1功能，efhc1-/-KO小鼠是否概括了CTC惊厥和“微发育不全”神经病理学，以及EFHC1过表达时，在果蝇模型中是否可以挽救多余的突触和树突表型。我们对证据的强度进行了评级，并应用ACMG组合标准对变体进行了分类。
九种变异被归类为“致病性，\“14作为\”可能是致病的，“9为”良性，\"和2为\"可能是良性的。“20个未知意义的变异体的祖先匹配对照数量不足，但与种族/族裔匹配的ExomeAggregationConsortium（ExAC）对照相比，OR超过5。
NHGRI基因水平的证据和变异水平的证据证明EFHC1是第一个非离子通道微管相关蛋白，其突变会干扰R型VDCC和TRPM2钙电流在异常迁移的神经元内过度生长的突触和树突中，从而解释了CTC惊厥和JME的“微发育不全”神经病理学。GenetMed192，144-156。
我们计算了共同继承中变体的贝叶斯LOD分数，病例对照关联中的无条件精确测试和优势比(OR)，基因组数据库中的等位基因频率，以及保守性/致病性的预测。我们回顾了变体是否会损害EFHC1功能，efhc1-/-KO小鼠是否概括了CTC惊厥和“微发育不全”神经病理学，以及EFHC1过表达时，在果蝇模型中是否可以挽救多余的突触和树突表型。我们对证据的强度进行了评级，并应用ACMG组合标准对变体进行了分类。
九种变异被归类为“致病性，\“14作为\”可能是致病的，“9为”良性，\"和2为\"可能是良性的。“20个未知意义的变异体的祖先匹配对照数量不足，但与种族/族裔匹配的ExomeAggregationConsortium（ExAC）对照相比，OR超过5。
NHGRI基因水平的证据和变异水平的证据证明EFHC1是第一个非离子通道微管相关蛋白，其突变会干扰R型VDCC和TRPM2钙电流在异常迁移的神经元内过度生长的突触和树突中，从而解释了CTC惊厥和JME的“微发育不全”神经病理学。GenetMed192，144-156。
