The Genetic Landscape of Pediatric Postural Orthostatic Tachycardia Syndrome

Background Postural orthostatic tachycardia syndrome (POTS) is a complex disorder with serious health consequences, while its etiology remains largely elusive. Objective To investigate the genetic landscape of POTS using genomic approaches in a unique pediatric cohort. Methods We conducted a combined genome wide genotyping and whole exome sequencing (WES) study to systemically examine the molecular mechanisms of POTS pathogenesis. The patients for were genotyped as two independent cohorts, a family cohort of 100 complete families and a case control cohort of 207 unrelated European cases and 4,063 ethnicity-matched controls. The WES component consisted of a subset of the genotyped subjects, including 87 unrelated European cases and 2,719 unrelated European controls. Results Due to the heterogeneous phenotype of POTS, unlike traditional phenotypes for association study, it is unlikely that any loci will reach genome-wide significance. Instead, we conducted an over-representation analysis (ORA) by considering all genes that showed nominal significance. The ORA identified gene sets linked to Cell-Cell Junction, Early Estrogen Response, and Substance-Related Disorders, with statistical significance. Moreover, WES revealed 55 genes with genome-wide significance through rare variant burden analysis, harboring 92 variants classified as pathogenic or likely pathogenic by ClinVar. Conclusions and Relevance This study showcases the complex interplay between common and rare genetic variants in POTS development, marking an pioneering step forward in deciphering its complex etiologies. The insights gained from this research enriches our understanding of POTS, offering new avenues for precise treatment strategies and highlighting the need for continued research in this area. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded in part by donation from the Esther Feigenbaum Foundation, The Siemer Family Foundation, by an Endowed Chair in Genomic Research (HH) and by an Institutional Development Award to the Center for Applied Genomics from The Children's Hospital of Philadelphia. ### 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: The Institutional Review Board (IRB) of the Children's Hospital of Philadelphia (CHOP) approved this 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 that support the findings of this study are available upon reasonable request to the corresponding author.