Next Article in Journal
Association Between E-Cigarette Use (Vaping) and Oral Health in Adolescents and Young Adults: A Systematic Review
Previous Article in Journal
Does the Type of Electrotherapy Impact the Effectiveness of Complex Physiotherapy Administered to Individuals with Neck Pain?
Previous Article in Special Issue
Gait Alterations in Flatfoot Compared to Healthy Controls: A Systematic Review and Meta-Analysis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 15
Issue 10
10.3390/jcm15103881
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Genetic Causes and Ankle Instability in Hypermobile Ehlers–Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging

by
Jae-Yoon Kim
1,2,†,
Ho-Yeon Lee
2,3,4,†,
Seon-Yeop Kim
1,2,
Sun-Woo Lee
1,2,
Minjoo Cho
1,2,
Jeong Woen Shin
1,2,
Yeo-Gyeong Yoon
1,2,
Jinhyuk Lee
2,4,
Yea Eun Kang
5,6,
Da Hyun Kang
5,6,
Seong Kyeong Jo
7,
Chan Kang
8,
Namshin Kim
4,* and
Jae Hwang Song
7,*
1
Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
2
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
3
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
4
Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
5
Research Center for Endocrine and Metabolic Disease, Integrated Disease Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
6
Department of Internal Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
7
Department of Orthopaedic Surgery, Konyang University Hospital, Daejeon 35365, Republic of Korea
8
Department of Orthopaedic Surgery, Chungnam National University, Daejeon 35015, Republic of Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2026, 15(10), 3881; https://doi.org/10.3390/jcm15103881
Submission received: 7 May 2026 / Accepted: 14 May 2026 / Published: 18 May 2026
(This article belongs to the Special Issue Foot and Ankle Surgery: Clinical Challenges and New Insights: 2nd Edition)
Versions Notes

Abstract

Background: Hypermobile Ehlers–Danlos 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–control 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 < 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 > A), ITIH2 (c.783C > G), and ADAM21 (c.397C > 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.
Keywords: ankle instability; exome sequencing; genetic predisposition to disease; hypermobile Ehlers–Danlos syndrome; stress ultrasonography ankle instability; exome sequencing; genetic predisposition to disease; hypermobile Ehlers–Danlos syndrome; stress ultrasonography

Share and Cite

MDPI and ACS Style

Kim, J.-Y.; Lee, H.-Y.; Kim, S.-Y.; Lee, S.-W.; Cho, M.; Shin, J.W.; Yoon, Y.-G.; Lee, J.; Kang, Y.E.; Kang, D.H.; et al. Genetic Causes and Ankle Instability in Hypermobile Ehlers–Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging. J. Clin. Med. 2026, 15, 3881. https://doi.org/10.3390/jcm15103881

AMA Style

Kim J-Y, Lee H-Y, Kim S-Y, Lee S-W, Cho M, Shin JW, Yoon Y-G, Lee J, Kang YE, Kang DH, et al. Genetic Causes and Ankle Instability in Hypermobile Ehlers–Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging. Journal of Clinical Medicine. 2026; 15(10):3881. https://doi.org/10.3390/jcm15103881

Chicago/Turabian Style

Kim, Jae-Yoon, Ho-Yeon Lee, Seon-Yeop Kim, Sun-Woo Lee, Minjoo Cho, Jeong Woen Shin, Yeo-Gyeong Yoon, Jinhyuk Lee, Yea Eun Kang, Da Hyun Kang, and et al. 2026. "Genetic Causes and Ankle Instability in Hypermobile Ehlers–Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging" Journal of Clinical Medicine 15, no. 10: 3881. https://doi.org/10.3390/jcm15103881

APA Style

Kim, J.-Y., Lee, H.-Y., Kim, S.-Y., Lee, S.-W., Cho, M., Shin, J. W., Yoon, Y.-G., Lee, J., Kang, Y. E., Kang, D. H., Jo, S. K., Kang, C., Kim, N., & Song, J. H. (2026). Genetic Causes and Ankle Instability in Hypermobile Ehlers–Danlos Syndrome (hEDS): An Integrated Analysis Using Whole-Exome Sequencing and Stress Imaging. Journal of Clinical Medicine, 15(10), 3881. https://doi.org/10.3390/jcm15103881

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop