Dr. Jeffrey Boris on the genetic landscape of POTS

Dr. Jeffrey Boris discusses his team’s large pediatric POTS genetics study using parent–child trios plus case–control cohorts with genotyping and whole-exome sequencing. They identified 55 genes with genome‑wide significance and additional pathogenic/likely pathogenic variants pointing to abnormalities in cell–cell junctions, cell membranes, transporters, cytoskeleton (actin/microtubules), extracellular matrix, and muscle contraction (including myosin), as well as signals tied to blood pressure/heart rate regulation. Collagen variants (e.g., COL7/12/27) support the known overlap with hypermobility/EDS. Early estrogen-response signals may help explain female predominance and perimenstrual flares. Variants linked to autism spectrum disorder and vestibular dysfunction also appeared; in his clinic ~9% of POTS patients carry an ASD diagnosis, and many have vestibular/convergence issues even without concussion. Findings are heterogeneous and not deterministic—next steps are functional studies of downstream proteins, potentially cross-linking with proteomics. Family data show aggregation (≈14% with a relative with POTS; ≈45% with a family history of autoimmune disease; ≈20–26% with family hypermobility). Clinically, 72% of females worsen around menses (mainly 10 days before through 5 days during); many benefit from low‑estrogen combined OCPs or low‑estrogen IUDs, and some from progestin‑only options. Non-drug neuromodulation via transcutaneous vagus nerve stimulation shows promise and may reduce IL‑6/TNF‑α, aligning with autoimmune/autoinflammatory mechanisms; MCAS (~71%) and joint hypermobility (~78%) are common in his cohort. He cautions about overdiagnosis from 1‑minute orthostatics and notes the dedicated ICD‑10 (and ICD‑11) POTS codes. Despite illness burden, long‑term outcomes show resilience: by age 21, 98% achieved a high school diploma/GED and ~80% attended college.