位于X染色体(Xp22.12)上的Ras-2激酶抑制剂(CNKSR2)的连接增强子中的致病变体导致以发育延迟和特征性癫痫发作表型为特征的疾病。迄今为止,已经发表了代表13种不同致病变体的20名受影响的雄性。
我们发现一名8岁男性癫痫发作,异常脑电图(EEG)与右半球的癫痫样异常,和发育迟缓,癫痫发作后出现明显的言语丧失。其他问题包括多次夜间觉醒,多动症,和自闭症谱系障碍。基因测试在CNKSR2中鉴定出从头致病性无义变体。通过一个积极的家庭支持小组,描述了另外12只雄性,每个都有不同的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,和癫痫发作在儿童期,最初是棘手的,但后来变得更好的控制。几乎所有的致病变异都被预测为功能丧失,包括基因组缺失,废话变体,剪接位点突变,和小的插入或删除。
这种扩展的知识,结合功能研究和目前正在进行的动物模型,将能够更好地理解和提高对CNKSR2相关神经发育和癫痫患者的护理能力。
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.