Pathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published. We identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2. Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions. This expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

中文翻译：

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CNKSR2 相关神经发育和癫痫疾病：13 个新家族的队列和文献综述表明功能丧失致病变异占主导地位


位于 X 染色体 (Xp22.12) 上的 Ras-2 激酶抑制因子连接器增强子 (CNKSR2) 的致病性变异会导致一种以发育迟缓和特征性癫痫表型为特征的疾病。迄今为止，已发表代表 13 种不同致病变异的 20 名受影响男性。我们发现一名 8 岁男性患有癫痫发作，脑电图 (EEG) 异常，右半球出现癫痫样异常，并且发育迟缓，癫痫发作后出现明显的言语丧失。其他问题包括多次夜间醒来、多动症和自闭症谱系障碍。基因测试发现了 CNKSR2 中的一个从头致病性无义变异。通过活跃的家庭支持小组，另外 12 名男性被描述，每名男性都携带不同的 CNKSR2 变体。临床表现和自然史一致显示早期发育迟缓、睡眠障碍和儿童期癫痫发作，最初难以治愈，但后来得到更好的控制。事实上，所有致病变异都被预测会丧失功能，包括基因组缺失、无义变异、剪接位点突变以及小插入或缺失。这些扩展的知识，与目前正在进行的功能研究和动物模型工作相结合，将有助于更好地理解和提高护理患有 CNKSR2 相关神经发育和癫痫疾病的个体的能力。