A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes

Abstract

A substantial fraction of the 15% with double-jointedness or hypermobility have the traditionally ascertained joint-skeletal, cutaneous, and cardiovascular symptoms of connective tissue dysplasia and its particular manifestation as Ehlers-Danlos syndrome (EDS). The holistic ascertainment of 120 findings in 1261 EDS patients added neuro-autonomic symptoms like headaches, muscle weakness, brain fog, chronic fatigue, dyspnea, and bowel irregularity to those of arthralgia and skin laxity, 15 of these symptoms shared with those of post-infectious SARS-CoV-2 (long COVID-19). Underlying articulo-autonomic mechanisms guided a clinical qualification protocol that qualified DNA variants in 317 genes as having diagnostic utility for EDS, six of them identical (F2-LIFR-NLRP3-STAT1-T1CAM1-TNFRSF13B) and eighteen similar to those modifying COVID-19 severity/EDS, including ADAMTS13/ADAMTS2-C3/C1R-IKBKG/IKBKAP-PIK3C3/PIK3R1-POLD4/POLG-TMPRSS2/TMPRSS6-WNT3/WNT10A. Also, contributing to EDS and COVID-19 severity were forty and three genes, respectively, impacting mitochondrial functions as well as parts of an overlapping gene network, or entome, that are hypothesized to mediate the cognitive-behavioral, neuro-autonomic, and immune-inflammatory alterations of connective tissue in these conditions. The further characterization of long COVID-19 natural history and genetic predisposition will be necessary before these parallels to EDS can be carefully delineated and translated into therapies.

Keywords: Ehlers–Danlos syndrome (EDS); collagen genes; connective tissue dysplasia; dysautonomia; genomic testing; long COVID-19; mitochondrial DNA; musculoskeletal disease; post-acute COVID-19 sequelae (PACS).

Figure 1

Clinical protocol for DNA variant qualification. Clinical DNA variant (column 4) and 1–4 + medical diagnostic utilities (last column) are added to consensus qualifications (column 2) as discussed in the text; DNA/protein change and gene abbreviations except for MTHFR (methylene tetrahydrofolate reductase) and HBB (beta-globin) are explained in Tables S2 and S3; single amino acid codes (A—alanine, D—aspartate, E—glutamate, I—isoleucine, L—leucine, M—methionine, P—proline, Q—glutamine, R—arginine, S—serine, T—threonine, X—stop, V—valine) used here; fs, frame-shift.

Figure 2

Genes relevant to EDS or COVID-19 infection by tissue element or product type. (A) Connective tissue element/process relations (box, Figure 2A bottom) are from associated diseases (Tables S2 and S3). COVID-19 percentages are those of 83 genes after 21 impacting viral-related processes were subtracted. (B) Gene product functions are explained in the legend to Table S2. COVID-19 percentages are of all 104 genes listed in Table S3 (the PNPLA3 gene associated with gastrointestinal disease is not listed). Colors indicate relative proportions for EDS (blue) and COVID19 (red). Significantly (p < 0.05) lower X/ higher ↑ proportions (see Methods).

Figure 3

Genes and symptoms related to EDS and COVID-19. Genes related to EDS (Table S2) and COVID-19 infection (Table S3) are envisioned as overlapping parts of a network (rhizome below) connected through pathogenic mechanisms (trunk sap, phloem) to common symptoms of EDS (Table S1) and long COVID-19 (canopy above). EDS symptom ranges are for females over age 10.5 years from the EDS1261database; long COVID percentages and ranges are taken from Figure 2 of the work by Deer et al. [37].