{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:39Z","timestamp":1785407499317,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Resettlement Fund for the new faculty of Konyang University Hospital"},{"id":[{"id":"https:\/\/ror.org\/01eksj726","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003715","name":"Korea Research Institute of Bioscience and Biotechnology","doi-asserted-by":"crossref","award":["KGM5192632"],"award-info":[{"award-number":["KGM5192632"]}],"id":[{"id":"10.13039\/501100003715","id-type":"DOI","asserted-by":"crossref"}]},{"award":["KGM5192632"],"award-info":[{"award-number":["KGM5192632"]}],"id":[{"id":"https:\/\/ror.org\/03ep23f07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Hypermobile Ehlers\u2013Danlos syndrome (hEDS), the most common EDS subtype, is characterized by chronic pain and joint laxity, yet no definitive causative genes or imaging-based diagnostic criteria have been established. This study investigated the genetic basis of hEDS using whole-exome sequencing (WES) and objectively evaluated ankle instability. Methods: We conducted an observational cohort study with a case\u2013control comparison, including 22 patients and a three-generation Korean family (six individuals, four affected) diagnosed with hEDS by the 2017 criteria. WES was performed; ankle laxity was assessed by the anterior drawer test (ADT), stress ultrasonography, and stress radiography. Healthy young adults (n = 24, Beighton score &lt; 5) from our previous study served as controls. Results: The hEDS cohort had a mean Beighton score of 8.5, with all participants reporting a family history of hypermobility and musculoskeletal complications. Family-based WES identified variants in CD44 (c.1516 + 1G &gt; A), ITIH2 (c.783C &gt; G), and ADAM21 (c.397C &gt; T) in all affected individuals. In 22 unrelated patients, 114 variants in 103 candidate genes were identified; 17 patients harbored variants in genes from the same pathways as the family-derived causative genes. Compared with controls, the hEDS group showed significantly greater manual ADT grade, anterior talofibular ligament (ATFL) length at rest and under stress, dynamic ATFL change, anterior talar translation, and talar tilt. Conclusions: These findings provide molecular evidence that hEDS is a multifactorial disorder involving interconnected biological pathways, and confirm ankle instability as a clinically meaningful diagnostic feature. These complementary approaches may improve diagnostic accuracy and provide insights into the prognosis and therapeutic strategies for hEDS.<\/jats:p>","DOI":"10.3390\/jcm15103881","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"3881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Causes and Ankle Instability in Hypermobile Ehlers\u2013Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-0998","authenticated-orcid":false,"given":"Jae-Yoon","family":"Kim","sequence":"first","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1026-1744","authenticated-orcid":false,"given":"Ho-Yeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"},{"name":"Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"},{"name":"Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-Yeop","family":"Kim","sequence":"additional","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjoo","family":"Cho","sequence":"additional","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-4080","authenticated-orcid":false,"given":"Jeong Woen","family":"Shin","sequence":"additional","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeo-Gyeong","family":"Yoon","sequence":"additional","affiliation":[{"name":"Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"},{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhyuk","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), School of Bioscience, University of Science and Technology (UST), Daejeon 34141, Republic of Korea"},{"name":"Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2012-3716","authenticated-orcid":false,"given":"Yea Eun","family":"Kang","sequence":"additional","affiliation":[{"name":"Research Center for Endocrine and Metabolic Disease, Integrated Disease Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea"},{"name":"Department of Internal Medicine, Chungnam National University, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3495-0931","authenticated-orcid":false,"given":"Da Hyun","family":"Kang","sequence":"additional","affiliation":[{"name":"Research Center for Endocrine and Metabolic Disease, Integrated Disease Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea"},{"name":"Department of Internal Medicine, Chungnam National University, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Kyeong","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Konyang University Hospital, Daejeon 35365, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Chungnam National University, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6361-274X","authenticated-orcid":false,"given":"Namshin","family":"Kim","sequence":"additional","affiliation":[{"name":"Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hwang","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Konyang University Hospital, Daejeon 35365, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","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. 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