Abstract 14779: Whole Exome Sequencing Study in Pediatric Postural Orthostatic Tachycardia Syndrome Unveils a Path Forward From Genes to Drugs

Introduction: Postural orthostatic tachycardia syndrome (POTS) is more common in Caucasian individuals with a positive family history, while the risk in females is ~4-times of that in males. To date, the etiology of POTS is poorly understood.

Hypothesis: Integrative sequencing and translational approaches to identify its genetic underpinning may better understand its pathogenesis and molecular mechanisms for the development of novel precision-based therapies.

Methods: We adopted exome sequencing to evaluate the etiology and molecular mechanisms of POTS. We examined a unique collection of 87 unrelated pediatric POTS cases (61 females and 26 males, 6~21 years old), using exome sequencing. Non-relationship between individuals were validated by genome wide genotyping and identity by descent (IBD) analysis.

Results: All the individuals were classified as European by principal component analysis (Figure 1). We identified 184 pathogenic (P) or likely pathogenic (LP) variants (in 162 genes). Sixty-eight (78%) cases have at least one P/LP variant. Each P/LP mutation is supported by a minimum of two databases, including ClinVar, InterVar or HGMD_Pro_2023.1. Over-representation analysis (ORA) by the DisGeNET approach showed the enriched gene sets of muscle hypotonia and epilepsy/seizures with statistical significance (FDR<E-10). Clinically, among the 87 WES patients, 41 (47%) suffered from chronic fatigue, and 13 (15%) patients have the symptoms of epilepsy, seizure or convulsion. A number of drug targets in these gene sets are highlighted, including vitamin D receptor, carbamoyl-phosphate synthase 1, methylmalonyl-CoA mutase, androgen receptor, and phenylalanine hydroxylase.

Conclusions: Our results suggests that chronic fatigue and epilepsy/seizure symptoms are comorbid symptoms in POTS patients, resulting from common genetic defects. Future precision-based therapies targeting these specific genetic defects may lead to improved outcome in POTS.