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Diagnosis of the commonest subtype, hypermobile Ehlers\u2013Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up\u2010to\u2010date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin\u2010X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out\u2010dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high\u2010throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers\u2013Danlos Genetic Evaluation (HEDGE) study.<\/jats:p>","DOI":"10.1111\/cge.14026","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T02:54:05Z","timestamp":1625453645000},"page":"20-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hypermobile\n                    <scp>Ehlers\u2013Danlos<\/scp>\n                    syndrome: A review and a critical appraisal of published genetic research to date"],"prefix":"10.1111","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7064-0773","authenticated-orcid":false,"given":"Kirsty","family":"Scicluna","sequence":"first","affiliation":[{"name":"Department of Applied Biomedical Science, Faculty of Health Sciences University of Malta  Msida Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7852-2701","authenticated-orcid":false,"given":"Melissa M.","family":"Formosa","sequence":"additional","affiliation":[{"name":"Department of Applied Biomedical Science, Faculty of Health Sciences University of Malta  Msida Malta"},{"name":"Centre for Molecular Medicine and Biobanking University of Malta  Msida Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-2874","authenticated-orcid":false,"given":"Rosienne","family":"Farrugia","sequence":"additional","affiliation":[{"name":"Department of Applied Biomedical Science, Faculty of Health Sciences University of Malta  Msida Malta"},{"name":"Centre for Molecular Medicine and Biobanking University of Malta  Msida Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-3055","authenticated-orcid":false,"given":"Isabella","family":"Borg","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Biobanking University of Malta  Msida Malta"},{"name":"Medical Genetics Unit, Department of Pathology Mater Dei Hospital  Msida Malta"},{"name":"Department of Pathology, Faculty of Medicine and Surgery University of Malta  Msida Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31552"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2005.00401.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61054"},{"issue":"1","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"e000790","DOI":"10.1136\/rmdopen-2018-000790","article-title":"Ehlers\u2010Danlos syndromes: state of the art on clinical practice guidelines","volume":"4","author":"Sulli A","year":"2018","journal-title":"RMD Open"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31429"},{"issue":"10","key":"e_1_2_10_7_1","first-page":"1722","article-title":"Severity classes in adults with hypermobile Ehlers\u2010Danlos syndrome\/hypermobility spectrum disorders: a pilot study of 105 Italian patients","volume":"58","author":"Copetti M","year":"2019","journal-title":"Rheumatology (Oxford)"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/828970"},{"key":"e_1_2_10_9_1","volume-title":"GeneReviews\u00ae","author":"Levy HP","year":"2018"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31538"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102410392606"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33585"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36293"},{"key":"e_1_2_10_14_1","first-page":"9","article-title":"Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers\u2010Danlos syndrome, hypermobility type)","volume":"29","author":"Castori M","year":"2011","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2015.04.002"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33231"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2017.10.001"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S64251"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31425"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-015-0549-7"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","unstructured":"CastoriM.Ehlers\u2010Danlos syndrome hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous articular and systemic manifestations. 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