Natural language processing and expert follow-up establishes tachycardia association with CDKL5 deficiency disorder

Purpose 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. Methods 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. Results 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 (OR 4.2, 95%CI 1.75-9.93, padj<0.001). We found a 99.6-fold enrichment of supraventricular tachycardia (SVT) in CDD encounter notes (padj < 0.001), which led to identification of two cases of fetal/neonatal onset SVT previously undescribed in CDD. Tachycardia in CDD individuals was associated with the presence of other autonomic symptoms (OR 5.63, 95%CI 1.08-40.3, p=0.038). Conclusions CDD is associated with tachycardia, potentially including early-onset supraventricular tachycardia. 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. ### Competing Interest Statement EPK serves on the scientific advisory board and as a speaker for Marinus Pharmaceuticals, Inc. The other authors report no conflict of interest related to this study. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by Cleveland Clinic IRB, approval ID 22-147. Informed consent was waived considering the retrospective nature of the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the findings of this study are available within the article and its supplementary material.