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.

Clinical-Genomic Analysis of 1261 Patients with Ehlers–Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome)

“…A prior report [ 14 ] describes how the 1979 EDS patients were evaluated ( Supplementary Materials Table S1 ) and how their DNA testing was coordinated ( Tables S2–S4 ). Only methods relevant to the current data are repeated or expanded here.…”

“…The 1979 EDS and 735 developmental disability patients having outpatient evaluations were entered into a password-protected MS Excel © GW patient database as described [ 11 , 14 , 27 ], approved by the North Texas IRB (centered at Medical City Hospital, Dallas, TX, USA) in 2014 (exempt protocol number 2014-054). The 1261 EDS patients with systematic evaluations were transferred to a deidentified EDS1261GW1-23 database that included only sex and age range demographics, type of evaluation, source of referral, detailed history–physical findings, and positive/negative but not specific DNA results.…”

“…Advantaging this genomic approach requires equally broad perspectives on diseases like Ehlers–Danlos syndrome (EDS, [ 4 ]), evaluating all of its joint (articular) and neurovascular (autonomic) [ 5 ] findings rather than the few highlighted by rare types [ 6 , 7 , 8 ]. If EDS is recognized in its most common form, affecting a significant portion of the 10 to 20 percent satisfying “double-jointed” criteria [ 1 , 9 ], then more studies will be added to those [ 10 , 11 , 12 , 13 , 14 ] finding multiple gene alterations in EDS patients.…”

“…The second anticipates the many functions of collagens, acting in immune [ 19 ], muscular [ 20 , 21 ], and inflammatory networks [ 22 ]. Third and most important for understanding EDS symptoms is the balance of orthostatic stability [ 23 ] with brain blood supply [ 24 ] that, when impaired, produces parallel findings of tissue dysplasia, skeletal deformation, and dysautonomia [ 11 , 14 , 25 , 26 , 27 ].…”

“…These clinical-genomic considerations combine to emphasize that multiple genes must be associated with connective tissue functions, variously encoding elements of encapsulation/flow (heart–vessel), matrix/structure (bone–blood–clotting), boundary/constraint (skin–muscle), activity/locomotion (joint–nerve–muscle), and autonomic regulation (circulation–immunity–inflammation). It is then expected that the genes altered in EDS will be accordingly diverse, with 317 of them suggested to participate in networks that include genes predisposing to COVID-19 severity and persistence [ 14 ]. Here, the hypothesis of polygenic/multifactorial contribution to EDS is examined by mapping these mutated genes to define their nuclear and mitochondrial chromosome locations, contrasting them with those found in patients with developmental disability, and then correlating their impacts on connective tissue elements with their effects on EDS finding profiles.…”