We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.

中文翻译：

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CDK19 的新变体与涉及智力障碍和癫痫性脑病的综合征有关。


我们鉴定了三个不相关的个​​体，其 CDK19 具有从头错义变异，编码主要调节基因转录的细胞周期蛋白依赖性激酶蛋白家族成员。这些个体表现出肌张力低下、整体发育迟缓、癫痫性脑病和畸形特征。 CDK19 在脊椎动物和无脊椎动物模型生物之间是保守的，但目前尚不清楚 CDK19 的异常是否与人类疾病相关。 CDK19 果蝇同源物 Cdk8 的缺失会导致幼虫死亡，而人 CDK19 参考 cDNA 的表达可抑制幼虫死亡。相比之下，在受影响个体中发现的 CDK19 p.Tyr32His 和 p.Thr196Ala 变体无法挽救 Cdk8 的丢失，并且表现为无效等位基因。此外，神经元 RNAi 介导的果蝇 Cdk8 敲低可导致半致死性。少数封闭的苍蝇表现出严重的癫痫发作和寿命缩短。两种表型均被 CDK19 参考 cDNA 的适度表达完全抑制，但两种变体的表达则不受抑制。最后，Cdk8 的缺失会导致幼虫神经肌肉接头 (NMJ) 处的纽扣和突触明显缺失。总之，我们的研究结果表明，人类 CDK19 完全取代了果蝇中 Cdk8 的功能，人类疾病相关的 CDK19 变体表现为强烈的功能丧失变体，而有害的 CDK19 变体是综合征性神经发育障碍的基础。