Autism and developmental disability caused by KCNQ3 gain-of-function variants
Autism and developmental disability caused by KCNQ3 gain-of-function variants
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DOI：
10.1002/ana.25522
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发表时间：
2019-08-01
影响因子：
11.2
通讯作者：
Cilio, M. Roberta
中科院分区：
文献类型：
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作者：
Sands, Tristan T.;Miceli, Francesco;Cilio, M. Roberta
目的最近的报道描述了单个神经发育障碍（NDD）个体携带杂合KCNQ3新生变异（dnv）。我们试图评估KCNQ3的致病变异是否会导致NDD，并阐明相关的表型和分子机制。方法通过国际合作对NDD和KCNQ3型dnv患者进行鉴定。通过临床评估、图表回顾、脑电图（EEG）记录和父母访谈来表征表型。通过膜片钳记录分析变异的体外功能后果。结果共对11例患者进行评估。他们在KCNQ3中有复发的杂合dnv，影响残基R230 （R230C、R230H、R230S）和R227 （R227Q）。所有患者均在生命的前2年内出现全面发育迟缓。大多数（8/11,73%）是非语言的或只有几个单词。所有患者都有自闭症特征，11人中有5人（45%）被诊断为自闭症谱系障碍（ASD）。在10岁之前进行的脑电图显示，11名儿童中有8名（73%）频繁出现睡眠激活的多灶性癫痫样放电。在1.5岁至6岁之间记录的9个孩子中，有6个（67%）在睡眠期间几乎连续出现峰值。有趣的是，大多数患者（9/11,82%）没有癫痫发作，没有患者在新生儿期发生癫痫发作。突变体KCNQ3通道的电压钳记录显示了功能获得（GoF）效应。KCNQ3中特定的GoF变异导致NDD、ASD和大量睡眠激活的尖峰。这种新的表型与KCNQ3部分功能丧失引起的自限性新生儿癫痫，以及KCNQ2 GoF引起的新生儿或婴儿癫痫性脑病形成对比。Ann neurol 2019；86:181 - 192
Objective Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Results Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Interpretation Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192