PDF(Pubmed)
Abstract：
CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
摘要：
CDKL5缺乏症（CDD）是一种X连锁的显性癫痫脑病，以早期发作和抗药性癫痫为特征，精神运动延迟，和轻微的面部特征。已经报道了使CDKL5失活或损害其蛋白质产物激酶活性的基因组变体，使下一代测序（NGS）和染色体微阵列分析（CMA）成为标准诊断测试。我们报告了一名女性儿童的CDD可疑病例，该女性儿童在NGS和CMA上的检测结果均为阴性，并带有X染色体从头间隔倒位。最近开发的基因组技术（光学基因组作图和全基因组测序）的使用使我们能够很好地表征断点，其中之一在内含子1处中断CDKL5。这是科学文献中报道的第五例CDD在X染色体上有结构重排，为这种类型的异常可以代表复发性致病机制的假设提供证据，其频率可能被低估了，它被标准技术所忽视。该疾病的分子病因的鉴定对于评估病理结果和更好地研究与耐药性相关的机制极为重要。为特定疗法的发展铺平了道路。在没有分子确认的情况下，所有出现CDD的病例都应考虑核型和基因组技术。
