Ivaniuk Alina, Boßelmann Christian M, Zhang Xiaoming, St John Mark, Taylor Sara C, Krishnaswamy Gokul, Milinovich Alex, Aziz Peter F, Pestana-Knight Elia, Lal Dennis
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH.
Genet Med Open. 2023 Nov 18;2:100842. doi: 10.1016/j.gimo.2023.100842. eCollection 2024.
CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy with multisystemic comorbidities. Cardiovascular involvement in CDD was shown in animal models but is yet poorly described in CDD cohorts.
We identified 38 individuals with genetically confirmed CDD through the Cleveland Clinic CDD specialty clinic and matched 190 individuals with non-genetic epilepsy to them as a comparison group. Natural language processing was applied to yield Human Phenotype Ontology (HPO) terms from medical records. We conducted HPO association testing and manual chart review to explore cardiovascular comorbidities associated with CDD.
We extracted 243,541 HPO terms from 30,512 medical encounters. Phenome-wide analysis confirmed well-established CDD phenotypes and identified association of tachycardia with CDD (Odds ratio 4.2, 95% confidence interval (CI) 1.75-9.93, < .001). We found a 99.6-fold enrichment of supraventricular tachycardia (SVT) in CDD encounter notes ( < .001), which led to identification of 2 cases of fetal/neonatal onset SVT previously undescribed in CDD. Tachycardia in CDD individuals was associated with the presence of other autonomic symptoms (Odds ratio 5.63, 95% CI 1.08-40.3, = .038).
CDD is associated with tachycardia, potentially including early-onset SVT. Alongside prospective validation studies, semiautomated genotype-phenotype analysis with matched controls is a scalable, rapid, and efficient approach for validating known and identifying novel phenotype associations.
CDKL5缺乏症（CDD）是一种伴有多系统合并症的发育性癫痫性脑病。动物模型显示CDD存在心血管系统受累情况，但在CDD队列研究中对此描述甚少。
我们通过克利夫兰诊所CDD专科门诊确定了38例基因确诊的CDD患者，并将190例非遗传性癫痫患者与之匹配作为对照组。应用自然语言处理技术从病历中提取人类表型本体（HPO）术语。我们进行了HPO关联测试和病历人工审查，以探索与CDD相关的心血管合并症。
我们从30512次医疗就诊记录中提取了243541个HPO术语。全表型分析证实了已明确的CDD表型，并确定心动过速与CDD相关（优势比4.2，95%置信区间（CI）1.75 - 9.93，P <.001）。我们发现CDD就诊记录中室上性心动过速（SVT）的富集度为99.6倍（P <.001），这导致发现了2例CDD中先前未描述的胎儿/新生儿期发作的SVT病例。CDD患者的心动过速与其他自主神经症状的存在相关（优势比5.63，95% CI 1.08 - 40.3，P =.038）。
CDD与心动过速相关，可能包括早发性SVT。除了前瞻性验证研究外，与匹配对照组进行的半自动基因型 - 表型分析是验证已知和识别新的表型关联的一种可扩展、快速且有效的方法。
