A gene network implicated in the joint-muscle pain, brain fog, chronic fatigue, and bowel irregularity of Ehlers-Danlos and 'long' COVID19 syndromes

ObjectivesCharacterization of tissue laxityanddysautonomia symptoms in Ehlers-Danlos syndrome (EDS) uncovered similarities with those of post-infectious SARS-CoV-2 or long COVID19, prompting detailed comparison of their findings and influencing genes.MethodsHolistic assessment of 1261 EDS outpatients for 120 history-physical findings populated a deidentified database that includes 568 patients with 317 variant genes obtained by commercial NextGen sequencing. Findings were compared to 15 of long COVID19 compiled in an extensive review, genes to 104 associated with COVID19 severity in multiple molecular studies.ResultsFifteen symptoms common to Ehlers-Danlos versus long COVID19 ranged from brain fog (27-80 versus 30-70%), chronic fatigue (38-91; 30-60%), dyspnea (32-52; 29-52%) to irritable bowel (67-89; 14-78%), muscle weakness (22-49; 15-25%), and arthritis (32-94; 15-27%). Genes relevant to EDS included 6 identical to those influencing COVID19 severity (F2,LIFR,NLRP3,STAT1,T1CAM1,TNFRSF13B) and 18 similar includingPOLG-POLD4,SLC6A2-SLC6A20, andNFKB1-NFKB2. Both gene sets had broad genomic distribution, many mitochondrial genes influencing EDS and many involved with immunity-inflammation modifying COVID19 severity. Recurring DNA variants in EDS that merit evaluation in COVID19 resistance include those impacting connective tissue elements--51 inCOL5(joint), 29 inCOL1/2/9/11(bone), 13 inCOL3(vessel), and 18 inFBN1(vessel-heart)--or neural function--93 in mitochondrial DNA, 28 inCOL6/12, 16 inSCN9A/10A/11A, 14 inPOLG, and 11 in genes associated with porphyria.ConclusionsHolistic ascertainment of finding pattern and exome variation in EDS defined tissue laxity, neuromuscular, and autonomic correlations that transcend single abnormalities or types. Implied networks of nuclear and mitochondrial genes are linked to findings like brain fog, fatigue, and frailty in EDS, their similarity to long COVID19 supporting shared therapies for disorders affecting a minimum 0.1% of the global population.