Ehlers-Danlos Syndrome (EDS) is a highly complex disorder encompassing a group of inherited genetic connective tissue disorders. EDS is caused by variants in genes involved in collagen structure, processing, and extracellular matrix integrity. It impacts multiple body systems and overlaps with numerous other disorders. Because of this, patients with EDS frequently experience long diagnostic delays, misdiagnoses, and underdiagnoses. Many diagnostic journeys last for years. Some extend through the lifetime due to fragmented or incomplete care.
The Role of Genome Sequencing in Diagnosing Ehlers-Danlos Syndrome
Historically, EDS evaluations relied on clinical criteria and biomarkers. The limited genetic panels ordered often left people without a precise or definitive diagnosis. Today, whole genome sequencing (WGS) offers the most comprehensive and accurate means of finding disease-causing variants, coexisting genetic conditions, and systemic manifestations. As technology has advanced and become more widely accessible, WGS has emerged as the gold standard for diagnosing hereditary connective tissue disorders and their mimics.
Benefits of a Genetic Diagnosis for EDS
Although there is currently no cure for EDS, pinpointing its molecular cause allows for:
- Targeted EDS management
- Personalized health surveillance
- Family risk assessment
Without genomic confirmation, conclusions are subjective and prone to error. In one study, more than half of patients with EDS had at least one misdiagnosis, with an average diagnostic delay of over 14 years. These experiences reflect the complex overlap between EDS and other genetic and acquired conditions.
EDS Case Insights from 2,500+ Patients
SequenceMD has evaluated more than 2,500 patients with suspected or diagnosed EDS. Our patient-centered genomic model contrasts with traditional, referral-based workflows that restrict testing to a single specialty or organ system. By having experienced clinical geneticists who are familiar with connective tissue and syndromic overlap that interprets all WGS results, that dramatically increases diagnostic precision and make to comprehensive precision management possible.
Among EDS cases, WGS evaluations have uncovered numerous alternative or additional molecular findings. Some evaluations revealed novel or incompletely characterized genetic disorders. These results show the limitations of relying solely on clinical diagnostic criteria and bio-markers They also emphasize the power of a genome-first approach to identify underlying or coexisting genetic causes.
Actionable Results: Around 40% of patients had actionable results beyond connective tissue genes, informing preventive and predictive care. These included secondary findings, pharmacogenomic insights to guide medication use, and carrier screening outcomes.
Diagnosis: Alternative or additional monogenic diagnoses with overlapping clinical features included vascular EDS, Marfan syndrome, FIG4-related neuropathy, and SPG7-related hereditary spastic paraplegia. These results highlight the genetic diversity and phenotypic mimicry of EDS-like disorders and the diagnostic value of genome-wide testing.
Unrelated Predispositions: In nearly 10% of patients referred for EDS evaluation, we found hereditary cancer predispositions unrelated to their connective tissue concern. These findings underscore the benefits of detailed family history review and comprehensive phenotyping (analyzing physical, observable traits, like appearance, behavior, and physiology).
Ongoing Reinterpretation: Over 50% of patients harbored variants of uncertain significance (VUS). Many of those were reclassified as likely pathogenic (or disease-causing) after correlation and reanalysis, reinforcing the need for ongoing variant tracking. Reinterpretation is central to our long-term diagnostic accuracy and care management.
Inheritance Patterns: Inheritance patterns depend on the EDS subtype and gene involved. Most forms follow an autosomal dominant pattern, where the parent has up to a 50% chance of passing the variant to each child.
“We start with the patient—not the referral—and let the phenotype guide the test, not the other way around.”
Our Patient-Centric Genome-First Approach
SequenceMD begins every genetic evaluation with the patient, not the referral. Rather than testing based on a single suspected diagnosis, each evaluation combines a full clinical history, cross-system findings, and family risk assessment.
Traditional workflows constrain testing to predefined panels or single systems, overlooking syndromic overlap and atypical presentations. Our integrative, cross-domain model evaluates each patient holistically, considering genetic, environmental, and familial factors. This philosophy enhances diagnostic yield, improves long-term care planning, and ensures equitable access to genomic medicine.
Our approach identifies the true etiology of the presenting traits and symptoms, confirming, refining, or ruling out known monogenic causes. Testing indications expand as additional risks are found (like family history of cancer prompting hereditary cancer testing). Through secondary and complementary testing (such as pharmacogenomics, carrier screening, and polygenic risk scoring), we build a complete genomic health profile for each patient.
Personalized Medicine and Care Every Time
By integrating whole genome sequencing, broad phenotyping, and cross-domain analysis, SequenceMD:
- Delivers diagnostic clarity, including providing the specific EDS subtype
- Uncovers hidden risks like other hereditary predispositions and comorbidities
- Guides personalized care, management strategies, and family counseling
Our experts provide detailed, evidence-based recommendations to primary care and referring providers, translating genomic findings into actionable clinical guidance. By collaborating and coordinating closely with care teams, we promote precision, continuity, and excellence in patient outcomes.
