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Considerations and Challenges in Genetic Testing for Hypermobile Ehlers-Danlos Syndrome (hEDS): A Multidisciplinary Overview

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Ehlers-Danlos Syndromes (EDS) are among the most prevalent hereditary connective tissue disorders (HCTDs), with molecular causes identified for 13 subtypes through variants in 20 distinct genes. However, the molecular basis of hypermobile EDS (hEDS) and hypermobility spectrum disorders (HSD) remains unknown. The "Diagnostic Checklist Criteria for hEDS" has been developed to assist in clinical diagnosis. Criterion 3 requires the exclusion of alternative diagnoses, including other HCTDs. The introduction of Exome Sequencing (ES) as a first-line diagnostic tool has recently enhanced the diagnostic yield for HCTDs and hEDS/HSD, offering improved patient follow-up and prognosis guidance. This study aimed to evaluate the role of ES in patients referred with a diagnosis of hEDS/HSD.

Case Presentation
A total of eighty-five mexican patients agreed to be enrolled in the study, all patients were diagnosed hEDS/HSD from January 2022 to November 2024, according to the "Diagnostic Checklist Criteria for hEDS" established by The International Consortium on EDS.

Diagnostic Workup
Orthopedic and genetic clinicians evaluated all patients. The team performed Exome Sequencing (ES) using short-read next-generation sequencing (NGS) with copy number variation (CNV) and mitochondrial DNA analysis on an Illumina platform, ensuring a minimum coverage depth of 20x for over 98% of targeted bases. All participants gave informed consent, and the team documented the clinical, molecular, and diagnostic findings.

 

Treatment and Management
The MEXEDS (México Ehlers-Danlos) working group performed genetic testing on 45 of the 85 patients, with 95% of the tested cohort being female. All patients were examined by the MEXEDS working group which includes a geneticist, orthopedic surgeon,  algologist, nutritionist, cardiologist, rheumatologist, urologist, and physiotherapist. Phenotypic variability was high, and clinicians identified several clinical features not previously associated with hEDS, including congenital cataracts, ADHD, anxiety disorders, and deficiencies in vitamin D, B12, and folate, as well as malabsorption and thyroid disorders.

Outcome and Follow-Up
Following  Exome Sequencing (ES) analysis, more than 80% of the cohort needed changes to their management and follow-up plans.

Discussion
Researchers divided the cohort into two groups: (a) Clinical Criteria only and (b) Clinical Criteria plus Exome Sequencing (ES). The mean age at diagnosis was 29 years (CI 8-51) for the Clinical Criteria group and 26 years (CI 6-50) for the Clinical Criteria plus ES group, with a mean age of symptom onset of 18 years (CI 5-45) versus 12 years (CI 2-40), respectively. ES produced a diagnostic yield of 23% for hereditary connective tissue disorders (HCTDs), identifying likely pathogenic or pathogenic variants in genes such as COL5A2, SMAD3, FLNA, SCN9A, TGFBR1, and TGFB3. The bioinformatic and raw-data analysis did not reveal any significant heterozygous variants in the TNXB gene, which researchers have associated recently with joint laxity and soft skin in some hEDS cases.​​ In this cohort, Loeys-Dietz syndrome emerged as a common differential diagnosis, especially in young patients not being evaluated for aortic disease. Additional findings in genes linked to chronic pain, muscle disease, headaches or migraines, joint hypermobility, or vesicoureteral reflux offered explanations for atypical hEDS phenotypes observed in these patients. Nearly all identified genetic variants were novel, with no existing records in major genetic databases like ClinVar or publications in PubMed, underscoring the uniqueness of these variants within this cohort.

Conclusion

  • Genetic assessment for hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) presents considerable challenges for physicians, especially in countries like Mexico, where financial limitations and restricted access to advanced diagnostic testing create significant barriers.

  • Expanding the recognized hEDS/HSD phenotype to incorporate clinical features not traditionally associated with these conditions, may improve diagnostic accuracy and treatment options.

  • The "Diagnostic Checklist Criteria for hEDS" developed by The International Consortium on EDS, highlights the importance of genetic testing to exclude other hereditary connective tissue disorders (HCTDs). Incorporating next-generation sequencing (NGS) techniques, such as Exome Sequencing (ES), into these diagnostic guidelines is essential in future practice.

  • Our findings indicate that beginning the diagnostic process with ES as a first-tier tool could enhance the cost-effectiveness and diagnostic reach for hEDS/HSD, enabling more precise and personalized follow-up care for each patient.




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