{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:51:09Z","timestamp":1790603469813,"version":"4.1.0"},"reference-count":119,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:00:00Z","timestamp":1689552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>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\u2013Danlos 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\u2013behavioral, 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.<\/jats:p>","DOI":"10.3390\/cimb45070379","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T01:07:39Z","timestamp":1689728859000},"page":"6003-6023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers\u2013Danlos and Long COVID-19 Syndromes"],"prefix":"10.3390","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-5256","authenticated-orcid":false,"given":"Golder N.","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, and KinderGenome Genetics Private Practice, 5347 W Mockingbird, Dallas, TX 75209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/gim.2016.14","article-title":"Targeted next-generation sequencing makes new molecular diagnoses and expands genotype\u2013phenotype relationship in Ehlers\u2013Danlos syndrome","volume":"18","author":"Weerakkody","year":"2016","journal-title":"Genet Med."},{"key":"ref_2","first-page":"181","article-title":"Genomic Analysis of 727 Patients with Ehlers-Danlos Syndrome I: Clinical Perspective Relates 23 Genes to a Maternally Influenced Arthritis-Adrenaline Disorder","volume":"7","author":"Wilson","year":"2019","journal-title":"J. Biosci. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.3390\/cimb44040099","article-title":"Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome","volume":"44","author":"Heise","year":"2022","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.mcna.2019.08.002","article-title":"Symptomatic joint hypermobility: The hypermobile type of Ehlers-Danlos syndrome and the hypermobility spec-trum disorders","volume":"103","author":"Tinkle","year":"2019","journal-title":"Med. Clin. North Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ajmg.c.31548","article-title":"Ehlers-Danlos syndrome, classical type","volume":"175","author":"Bowen","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/ajmg.c.31553","article-title":"Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome","volume":"175","author":"Byers","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/0021-9681(55)90148-X","article-title":"Heritable disorders of connective tissue: I. The clinical behavior of hereditary syndromes","volume":"2","author":"McKusick","year":"1955","journal-title":"J. Chronic Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0002-9343(03)00235-3","article-title":"Dysautonomia in the joint hypermobility syndrome","volume":"115","author":"Gazit","year":"2003","journal-title":"Am. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.semarthrit.2013.12.006","article-title":"Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers\u2013Danlos syndrome","volume":"44","author":"Rombaut","year":"2014","journal-title":"Semin. Arthr. Rheum."},{"key":"ref_11","first-page":"149","article-title":"Clinical Analysis Supports Articulo-Autonomic Dysplasia as a Unifying Pathogenic Mechanism in Ehlers-Danlos Syndrome and Related Conditions","volume":"7","author":"Wilson","year":"2019","journal-title":"J. Biosci. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1212\/WNL.0000000000002847","article-title":"Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes","volume":"87","author":"Cazzato","year":"2016","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/ajmg.c.31549","article-title":"Neurological and spinal manifestations of the Ehlers-Danlos syndromes","volume":"175","author":"Henderson","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.bbrc.2012.11.119","article-title":"The vWFA2 domain of type VII collagen is responsible for collagen binding","volume":"430","author":"Wegener","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1182\/blood-2006-03-011965","article-title":"A single high-affinity binding site for von Willebrand factor in collagen III, identified using synthetic triple-helical peptides","volume":"108","author":"Lisman","year":"2006","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.3390\/ijms16035635","article-title":"Molecular Mechanisms Underlying \u03b2-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells","volume":"16","author":"Lorton","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"190","DOI":"10.5296\/jbls.v11i2.17756","article-title":"Mitochondrial Dysfunction Contributes to Ehlers-Danlos Syndrome\u2014A Patient Presentation","volume":"11","author":"Wilson","year":"2020","journal-title":"J. Biol. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s10048-019-00593-2","article-title":"Infectious stress triggers a POLG-related mitochondrial disease","volume":"21","author":"Emperador","year":"2020","journal-title":"Neurogenetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102828","DOI":"10.1016\/j.autneu.2021.102828","article-title":"Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting\u20141","volume":"235","author":"Vernino","year":"2021","journal-title":"Auton. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.mayocp.2012.08.013","article-title":"Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder","volume":"87","author":"Benarroch","year":"2012","journal-title":"Mayo Clin. Proc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2500\/aap.2021.42.210022","article-title":"The relationship between mast cell activation syndrome, postural tachycardia syndrome, and Ehlers-Danlos syndrome","volume":"42","author":"Wang","year":"2021","journal-title":"Allergy Asthma Proc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s12026-022-09280-1","article-title":"Association of mast-cell-related conditions with hypermobile syn-dromes: A review of the literature","volume":"70","author":"Monaco","year":"2022","journal-title":"Immunol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, S.Z., Wang, Q.Q., Yang, Q.Q., Gu, H.Y., Yin, Y.Q., Li, Y.D., Hou, J.-C., Chen, R., Sun, Q.-Q., and Sun, Y.-F. (2019). NG2 glia regulate brain innate immunity via TGF-\u03b22\/TGFBR2 axis. BMC Med., 17.","DOI":"10.1186\/s12916-019-1439-x"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1111\/jgh.15927","article-title":"Hypermobile Ehlers\u2013Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know","volume":"37","author":"Thwaites","year":"2022","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103722","DOI":"10.1016\/j.ebiom.2021.103722","article-title":"Characterizing Long COVID: Deep Phenotype of a Complex Condition","volume":"74","author":"Deer","year":"2021","journal-title":"Ebiomedicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e63","DOI":"10.7861\/clinmed.2020-0896","article-title":"Autonomic dysfunction in \u2018long COVID\u2019: Rationale, physiology and management strategies","volume":"21","author":"Dani","year":"2020","journal-title":"Clin. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s10286-021-00798-2","article-title":"Long-COVID postural tachycardia syndrome: An American Autonomic Society statement","volume":"31","author":"Raj","year":"2021","journal-title":"Clin. Auton. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.bbi.2021.12.020","article-title":"Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis","volume":"101","author":"Ceban","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103071","DOI":"10.1016\/j.autrev.2022.103071","article-title":"The autonomic aspects of the post-COVID19 syndrome","volume":"21","author":"Dotan","year":"2022","journal-title":"Autoimmun. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12985-022-01891-2","article-title":"Pathophysiology of Post-COVID syndromes: A new perspective","volume":"19","author":"Batiha","year":"2022","journal-title":"Virol. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1001\/jama.2023.8823","article-title":"Recover Consortium. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection","volume":"329","author":"Thaweethai","year":"2023","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Global Burden of Disease Long COVID Collaborators, Wulf Hanson, S., Abbafati, C., Aerts, J.G., Al-Aly, Z., Ashbaugh, C., Ballouz, T., Blyuss, O., Bobkova, P., and Bonsel, G. (2022). Estimated Global Proportions of Individuals with Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters following Symptomatic COVID-19 in 2020 and 2021. JAMA, 328, 1604\u20131615.","DOI":"10.1001\/jama.2022.18931"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"410","DOI":"10.3389\/fcell.2020.00410","article-title":"New Insights of Emerging SARS-CoV-2: Epidemiology, Etiology, Clinical Features, Clinical Treatment, and Prevention","volume":"8","author":"Guo","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_34","unstructured":"(2023, January 22). World Health Organization. Available online: https:\/\/covid19.who.int."},{"key":"ref_35","first-page":"e27633","article-title":"Neurological Complications of COVID-19: A Review of the Literature","volume":"14","author":"Dale","year":"2022","journal-title":"Cureus"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1097\/HJH.0000000000003213","article-title":"Preeclampsia and severe acute respiratory syndrome coronavirus 2 infection: A systematic review","volume":"40","author":"Tossetta","year":"2022","journal-title":"J. Hypertens."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/apm.13210","article-title":"Could SARS-CoV-2 infection affect male fertility and sexuality?","volume":"130","author":"Finocchi","year":"2022","journal-title":"Apmis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1017\/thg.2020.85","article-title":"Self-Reported Symptoms of COVID-19, Including Symptoms Most Predictive of SARS-CoV-2 Infection, Are Heritable","volume":"23","author":"Williams","year":"2020","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eabl4348","DOI":"10.1126\/sciimmunol.abl4348","article-title":"X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19","volume":"6","author":"Asano","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ishaq, U., Malik, A., Malik, J., Mehmood, A., Qureshi, A., Laique, T., Zaidi, S.M.J., Javaid, M., and Rana, A.S. (2021). Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality. PLoS ONE, 16.","DOI":"10.1101\/2021.04.19.21255738"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Dieter, C., Brondani, L.A., Leit\u00e3o, C.B., Gerchman, F., Lemos, N.E., and Crispim, D. (2022). Genetic polymorphisms associated with susceptibility to COVID-19 disease and severity: A systematic review and meta-analysis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0270627"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104126","DOI":"10.1016\/j.compbiomed.2020.104126","article-title":"Determining crucial genes associated with COVID-19 based on COPD Findings","volume":"128","author":"Sharma","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s10456-021-09789-3","article-title":"Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: Insight from VWF\/ADAMTS13 ratio imbalance","volume":"24","author":"Philippe","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1055\/s-0041-1727282","article-title":"Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis","volume":"47","author":"Favaloro","year":"2021","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lynch, S.M., Guo, G., Gibson, D.S., Bjourson, A.J., and Rai, T.S. (2021). Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease. Cells, 10.","DOI":"10.3390\/cells10123367"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Amital, M., Ben-Shabat, N., Amital, H., Buskila, D., Cohen, A.D., and Amital, D. (2021). COVID-19 associated hospitalization in 571 patients with fibromyalgia\u2014A population-based study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0261772"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jtos.2021.10.010","article-title":"Small fiber neuropathy in the cornea of Covid-19 patients associated with the generation of ocular surface disease","volume":"23","author":"Barros","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e885","DOI":"10.1097\/PR9.0000000000000885","article-title":"Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: Implications for COVID-19 and pain","volume":"6","author":"McFarland","year":"2021","journal-title":"PAIN Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"D\u00edaz-Alberola, I., Espuch-Oliver, A., Garc\u00eda-Aznar, J.M., Ganoza-Gallardo, C., Aguilera-Franco, M., Sampedro, A., Jim\u00e9nez, P., and L\u00f3pez-Nevot, M. (2022). Common Variable Immunodeficiency Associated with a De Novo IKZF1 Variant and a Low Humoral Immune Response to the SARS-CoV-2 Vaccine. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092303"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"102314","DOI":"10.1016\/j.tmaid.2022.102314","article-title":"Systematic review of COVID-19 and autoimmune thyroiditis","volume":"47","author":"Tutal","year":"2022","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/gim.2013.73","article-title":"American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing","volume":"15","author":"Green","year":"2013","journal-title":"Genet. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrg3031","article-title":"Exome sequencing as a tool for Mendelian disease gene discovery","volume":"12","author":"Bamshad","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1056\/NEJMoa1306555","article-title":"Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders","volume":"369","author":"Yang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Wyandt, H.E., Wilson, G.N., and Tonk, V.S. (2017). Chromosome Structure and Variation: Heteromorphism, Polymorphism, and Pathogenesis, Springer Nature. Chapters 9\u201310.","DOI":"10.1007\/978-981-10-3035-2"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/gim.2014.160","article-title":"Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort","volume":"17","author":"Retterer","year":"2015","journal-title":"Genet Med."},{"key":"ref_56","unstructured":"Wilson, G.N. (2023). A network of genes (entome) is responsible for congruent tissue laxity and dysautonomia findings in hypermobility spectrum\/Ehlers-Danlos syndrome disorders, Manuscript in preparation."},{"key":"ref_57","unstructured":"MedCalc Software Ltd. (2023, January 22). Available online: https:\/\/www.medcalc.org\/calc."},{"key":"ref_58","unstructured":"Ehlers-Danlos Society (2023, January 22). Criteria for EDS types. Available online: https:\/\/www.ehlers-danlos.com\/2017-eds-international-classification\/."},{"key":"ref_59","unstructured":"The Ehlers-Danlos Society (2023, January 22). Beighton Maneuvers Illustrated. Available online: https:\/\/www.ehlers-danlos.com\/assessing-joint-hypermobility\/."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/ajmg.c.31958","article-title":"Orthopedic considerations and surgical outcomes in Ehlers\u2013Danlos syndromes","volume":"187","author":"Yonko","year":"2021","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ng, P.C., Levy, S., Huang, J., Stockwell, T.B., Walenz, B.P., Li, K., Axelrod, N., Busam, D.A., Strausberg, R.L., and Venter, J.C. (2008). Genetic Variation in an Individual Human Exome. PLOS Genet., 4.","DOI":"10.1371\/journal.pgen.1000160"},{"key":"ref_62","unstructured":"Wilson, G.N., and Tonk, V.S. A protocol for qualifying DNA variants associated with complex diseases like Ehlers-Danlos syndrome, GEN Protocols 2021\u2014An open access component of the genengnews.com website that has now been discontinued."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"24","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4033","DOI":"10.1016\/j.csbj.2020.11.041","article-title":"Combining Ramachandran plot and molecular dynamics simulation for structural-based variant classification: Using TP53 variants as model","volume":"18","author":"Tam","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_66","unstructured":"(2023, January 22). Genome Browser, University of California Santa Clara. Available online: https:\/\/genome.ucsc.edu\/."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1002\/humu.23858","article-title":"VIPdb, a genetic Variant Impact Predictor Database","volume":"40","author":"Hu","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_68","unstructured":"(2023, January 22). ClinVar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_69","unstructured":"(2023, January 22). MITOMAP: A Human Mitochondrial Genome Database. Available online: http:\/\/www.mitomap.org."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_71","unstructured":"(2023, January 22). Gnomad. Available online: https:\/\/gnomad.broadinstitute.org\/."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"eabc1404","DOI":"10.1126\/sciadv.abc1404","article-title":"A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase","volume":"6","author":"Noda","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/jmv.26319","article-title":"ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain","volume":"93","author":"Pytel","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-020-03065-y","article-title":"Genetic mechanisms of critical illness in COVID-19","volume":"591","author":"Clohisey","year":"2021","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1074\/jbc.M109.068726","article-title":"Location of 3-Hydroxyproline Residues in Collagen Types I, II, III, and V\/XI Implies a Role in Fibril Supramolecular Assembly","volume":"285","author":"Weis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_77","unstructured":"(2023, January 22). Human Phenotype Ontology. Available online: https:\/\/hpo.jax.org\/app\/."},{"key":"ref_78","first-page":"1","article-title":"Demon Genes May Deform Common Syndromes: Collagen VI Gene Change in Down Syndrome Unifies the Medical and Molecular Approach to Hypermobility Disorders","volume":"10","author":"Wilson","year":"2020","journal-title":"J. Biosci. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bcmd.2017.06.004","article-title":"Variability of homozygous sickle cell disease: The role of alpha and beta globin chain variation and other factors","volume":"70","author":"Serjeant","year":"2018","journal-title":"Blood Cells, Mol. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wo\u017aniak, E., Owczarczyk-Saczonek, A., Lange, M., Czarny, J., Wygonowska, E., Placek, W., and Nedoszytko, B. (2023). The Role of Mast Cells in the Induction and Maintenance of Inflammation in Selected Skin Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087021"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00431-014-2429-9","article-title":"Kyphoscoliotic type of Ehlers-Danlos Syndrome (EDS VIA) in six Egyptian patients presenting with a homogeneous clinical phenotype","volume":"174","author":"Abdalla","year":"2015","journal-title":"Eur. J. Pediatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1056\/NEJMp1904511","article-title":"Has the Genome Granted Our Wish Yet?","volume":"380","author":"Hunter","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1172\/JCI120842","article-title":"The role of mitochondria in aging","volume":"128","author":"Jang","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s00011-020-01389-z","article-title":"Coronavirus (Covid-19) sepsis: Revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality","volume":"69","author":"Shenoy","year":"2020","journal-title":"Inflamm. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/s41423-020-0480-1","article-title":"The essential functions of mitochondrial dynamics in immune cells","volume":"17","author":"Xie","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.cmet.2019.11.021","article-title":"Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function","volume":"31","author":"Field","year":"2020","journal-title":"Cell Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1001\/jama.2022.11238","article-title":"Patient-Reported Outcome Measures in Clinical Research","volume":"328","author":"Weinfurt","year":"2022","journal-title":"JAMA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/s41584-020-00565-z","article-title":"The impact of COVID-19 on rare and complex connective tissue diseases: The experience of ERN ReCONNET","volume":"17","author":"Talarico","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_89","first-page":"1","article-title":"Do severe complications like aneurysms from Kawasaki and Kawasaki-like infections arise in children with underlying articulo-autonomic dysplasia\/Ehlers-Danlos syndrome?","volume":"4","author":"Wilson","year":"2020","journal-title":"Ann. Ped. Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"D\u2019agnelli, S., Arendt-Nielsen, L., Gerra, M.C., Zatorri, K., Boggiani, L., Baciarello, M., and Bignami, E. (2018). Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers. Mol. Pain, 15.","DOI":"10.1177\/1744806918819944"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Yue, F., Era, T., Yamaguchi, T., and Kosho, T. (2023). Pathophysiological Investigation of Skeletal Deformities of Musculocontractural Ehlers\u2013Danlos Syndrome Using Induced Pluripotent Stem Cells. Genes, 14.","DOI":"10.3390\/genes14030730"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/978-1-0716-2309-1_10","article-title":"Measuring Mitochondrial Function: From Organelle to Organism","volume":"2497","author":"Lewis","year":"2022","journal-title":"Methods Mol Biol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Gr\u00fcnewald, A., Voges, L., Rakovic, A., Kasten, M., Vandebona, H., Hemmelmann, C., Lohmann, K., Orolicki, S., Ramirez, A., and Schapira, A.H.V. (2010). Mutant Parkin Impairs Mitochondrial Function and Morphology in Human Fibroblasts. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012962"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1072764","DOI":"10.3389\/fmed.2022.1072764","article-title":"Presentation and physical therapy management of upper cervical instability in patients with symptomatic generalized joint hypermobility: International expert consensus recommendations","volume":"9","author":"Russek","year":"2023","journal-title":"Front. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1249\/JSR.0b013e318223cc9e","article-title":"Review of the Role of Exercise in Improving Quality of Life in Healthy Individuals and in Those with Chronic Diseases","volume":"10","author":"Mitchell","year":"2011","journal-title":"Curr. Sports Med. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41586-020-1978-5","article-title":"The promise and challenge of therapeutic genome editing","volume":"578","author":"Doudna","year":"2020","journal-title":"Nature"},{"key":"ref_97","first-page":"601","article-title":"A Systemic Review of Adult Mesenchymal Stem Cell Sources and their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration","volume":"12","author":"Mafi","year":"2017","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1001\/jama.2020.13719","article-title":"Presence of genetic variants among young men with severe COVID-19","volume":"324","author":"Simons","year":"2020","journal-title":"JAMA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41586-021-03570-8","article-title":"COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets","volume":"595","author":"Delorey","year":"2021","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/s41586-022-05163-5","article-title":"DOCK2 is involved in the host genetics and biology of severe COVID-19","volume":"609","author":"Namkoong","year":"2022","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"COVID-19 Host Genetics Initiative (2021). Mapping the human genetic architecture of COVID-19. Nature, 600, 472\u2013477.","DOI":"10.1038\/s41586-021-03767-x"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1038\/s42255-021-00479-4","article-title":"Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication","volume":"3","author":"Chu","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"402","DOI":"10.7150\/ijms.67815","article-title":"Potential genes associated with COVID-19 and comorbidity","volume":"19","author":"Feng","year":"2022","journal-title":"Int. J. Med. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"103246","DOI":"10.1016\/j.ebiom.2021.103246","article-title":"Shorter androgen receptor polyQ alleles protect against life-threatening COVID19 disease in European males","volume":"65","author":"Baldassarri","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.cell.2020.10.030","article-title":"Identification of required host factors for SARS-CoV-2 infection in human cells","volume":"184","author":"Daniloski","year":"2021","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.jaci.2021.11.004","article-title":"Severe COVID-19 is associated with hyperactivation of the alternative complement pathway","volume":"149","author":"Boussier","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e152386","DOI":"10.1172\/JCI152386","article-title":"Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality","volume":"131","author":"Nakanishi","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41576-022-00478-5","article-title":"The human genetic epidemiology of COVID-19","volume":"23","author":"Niemi","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"eabd4585","DOI":"10.1126\/science.abd4585","article-title":"Autoantibodies against type I IFNs in patients with life-threatening COVID-19","volume":"370","author":"Bastard","year":"2020","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"eabd4570","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"21185","DOI":"10.1038\/s41598-021-00747-z","article-title":"IFNL4 genetic variant can predispose to COVID-19","volume":"11","author":"Rivas","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1038\/s41436-021-01243-5","article-title":"An integrative multiomics analysis identifies putative causal genes for COVID-19 severity","volume":"23","author":"Wu","year":"2021","journal-title":"Genet. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/s42003-021-02549-5","article-title":"Trans-ethnic genome-wide association study of severe COVID-19","volume":"4","author":"Wu","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.jaci.2021.01.006","article-title":"Associations between COVID-19 and skin conditions identified through epidemiology and genomic studies","volume":"147","author":"Patrick","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41419-021-04012-z","article-title":"RBM15-mediated N6-methyladenosine modification affects COVID-19 severity by regulating the expression of multitarget genes","volume":"12","author":"Meng","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"627914","DOI":"10.3389\/fcell.2021.627914","article-title":"PNPLA3 and TLL-1 polymorphisms as potential predictors of disease severity in patients with COVID-19","volume":"9","author":"Grimaudo","year":"2021","journal-title":"Front. Cell. Dev. Biol"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Latini, A., Agolini, E., Novelli, A., Borgiani, P., Giannini, R., Gravina, P., Smarrazzo, A., Dauri, M., Andreoni, M., and Rogliani, P. (2020). COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells. Genes, 11.","DOI":"10.3390\/genes11091010"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41421-020-00231-4","article-title":"Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility","volume":"6","author":"Wang","year":"2020","journal-title":"Cell Discov."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41588-022-01131-x","article-title":"Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection","volume":"54","author":"Biering","year":"2022","journal-title":"Nat. Genet."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/7\/379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:13:38Z","timestamp":1760127218000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/7\/379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,17]]},"references-count":119,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cimb45070379"],"URL":"https:\/\/doi.org\/10.3390\/cimb45070379","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,17]]}}}