Diagnostic Yield and Clinical Decision-Making in Hereditary Connective Tissue Disorders: Insights from an Adult Genetics Clinic
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Hereditary connective tissue disorders (HCTDs) present complex diagnostic challenges due to their overlapping phenotypes, variable expressivity, and sometimes unclear underlying genetic etiology. Accurate diagnosis is essential for effective patient management, yet genetic evaluation practices vary widely due to provider preferences, institutional policies, and insurance coverage. Consequently, patients with similar presentations may receive differing testing approaches or none at all. In addition, despite advances in genetic testing, confirmation of diagnosis remains challenging, especially when test results yield negative findings and variants of uncertain significance (VUS). This study aims to examine the testing practices, diagnostic yield, and clinical impact of genetic testing for patients referred for HCTD evaluation in a large county health system, exploring the factors influencing testing decisions and the outcomes of those tests.
Methods:
We conducted a retrospective analysis of 152 patients seen in our genetics clinics between 2014 and 2024, all referred for suspected HCTDs. Data collected included referral reasons, phenotypes, prior genetic testing, clinician assessments of genetic testing necessity, testing types, and results (positive, negative, or VUS). Additionally, we recorded the final clinical diagnoses, categorized as confirmed HCTDs, HCTD exclusions, or uncertain diagnoses. Statistical analyses evaluated associations among referral indications, genetic testing, testing outcomes, and final diagnoses, focusing on the utility of genetic testing in informing clinical decisions.
Results:
Of the 152 patients evaluated, 6 had prior genetic testing, 25 were deemed not to require testing, and 121 were recommended for testing. Of these, 110 completed testing, while others declined, faced financial or insurance barriers, or were lost to follow-up. Among the 110 tested, 8 underwent single/two-gene testing (4 KFM, 4 targeted genes), 1 had exome sequencing, and the rest had panel testing. 92.7% of panel testing was performed by Invitae, with the most common panels being Ehlers-Danlos Syndrome (EDS), aortopathy, and connective tissue disease (CTD), which includes genes associated with EDS, aortopathy, Marfan syndrome, osteogenesis imperfecta, and related disorders.
Of the 110 tested, 13.6% had positive results, 60.9% were negative, and 25.5% had variants of uncertain significance (VUS). Positive results identified HCTD-related genes such as COL1A1, COL1A2, COL2A1, COL5A1, FBN1, FBN2, SMAD4, and TGFB2, with all cases resulting in formal CTD diagnoses. Among VUS results, 17.8% were diagnosed with a CTD (4 hypermobile Ehlers-Danlos syndrome [hEDS] and 1 suspected pathogenic VUS), 28.6% ruled out, and 53.6% remained uncertain. Among negative results, 31.3% were diagnosed with a CTD (20 hEDS and 1 classical EDS), 49.3% ruled out, and 19.4% remained uncertain.
Of the 11 patients recommended for but not completing testing, 1 was diagnosed with hEDS after declining testing, while 10 remained with uncertain diagnoses. Among the 25 patients not recommended for genetic testing, 36% were diagnosed with a CTD (all hEDS), 56% were ruled out, and 8% were classified as uncertain, with hypermobility spectrum disorder.
Conclusion:
This study highlights the complexities of genetic testing and interpretation in hereditary connective tissue disorders (HCTDs), particularly in cases where standardized clinical criteria exist but are not consistently utilized. Our study also highlights variability in testing strategies even for similar presentations. Positive genetic findings played a critical role in confirming diagnoses, while negative results were valuable in both ruling out HCTDs with low pre-test probabilities and supporting diagnoses like hEDS. However, some patients remained without definitive diagnoses, and variants of uncertain significance (VUS) further complicated clinical interpretation. By clarifying the impact of genetic testing on clinical decision-making for HCTDs, our findings offer valuable insights for optimizing testing strategies, counseling, and patient management in clinical practice.
Hereditary connective tissue disorders (HCTDs) present complex diagnostic challenges due to their overlapping phenotypes, variable expressivity, and sometimes unclear underlying genetic etiology. Accurate diagnosis is essential for effective patient management, yet genetic evaluation practices vary widely due to provider preferences, institutional policies, and insurance coverage. Consequently, patients with similar presentations may receive differing testing approaches or none at all. In addition, despite advances in genetic testing, confirmation of diagnosis remains challenging, especially when test results yield negative findings and variants of uncertain significance (VUS). This study aims to examine the testing practices, diagnostic yield, and clinical impact of genetic testing for patients referred for HCTD evaluation in a large county health system, exploring the factors influencing testing decisions and the outcomes of those tests.
Methods:
We conducted a retrospective analysis of 152 patients seen in our genetics clinics between 2014 and 2024, all referred for suspected HCTDs. Data collected included referral reasons, phenotypes, prior genetic testing, clinician assessments of genetic testing necessity, testing types, and results (positive, negative, or VUS). Additionally, we recorded the final clinical diagnoses, categorized as confirmed HCTDs, HCTD exclusions, or uncertain diagnoses. Statistical analyses evaluated associations among referral indications, genetic testing, testing outcomes, and final diagnoses, focusing on the utility of genetic testing in informing clinical decisions.
Results:
Of the 152 patients evaluated, 6 had prior genetic testing, 25 were deemed not to require testing, and 121 were recommended for testing. Of these, 110 completed testing, while others declined, faced financial or insurance barriers, or were lost to follow-up. Among the 110 tested, 8 underwent single/two-gene testing (4 KFM, 4 targeted genes), 1 had exome sequencing, and the rest had panel testing. 92.7% of panel testing was performed by Invitae, with the most common panels being Ehlers-Danlos Syndrome (EDS), aortopathy, and connective tissue disease (CTD), which includes genes associated with EDS, aortopathy, Marfan syndrome, osteogenesis imperfecta, and related disorders.
Of the 110 tested, 13.6% had positive results, 60.9% were negative, and 25.5% had variants of uncertain significance (VUS). Positive results identified HCTD-related genes such as COL1A1, COL1A2, COL2A1, COL5A1, FBN1, FBN2, SMAD4, and TGFB2, with all cases resulting in formal CTD diagnoses. Among VUS results, 17.8% were diagnosed with a CTD (4 hypermobile Ehlers-Danlos syndrome [hEDS] and 1 suspected pathogenic VUS), 28.6% ruled out, and 53.6% remained uncertain. Among negative results, 31.3% were diagnosed with a CTD (20 hEDS and 1 classical EDS), 49.3% ruled out, and 19.4% remained uncertain.
Of the 11 patients recommended for but not completing testing, 1 was diagnosed with hEDS after declining testing, while 10 remained with uncertain diagnoses. Among the 25 patients not recommended for genetic testing, 36% were diagnosed with a CTD (all hEDS), 56% were ruled out, and 8% were classified as uncertain, with hypermobility spectrum disorder.
Conclusion:
This study highlights the complexities of genetic testing and interpretation in hereditary connective tissue disorders (HCTDs), particularly in cases where standardized clinical criteria exist but are not consistently utilized. Our study also highlights variability in testing strategies even for similar presentations. Positive genetic findings played a critical role in confirming diagnoses, while negative results were valuable in both ruling out HCTDs with low pre-test probabilities and supporting diagnoses like hEDS. However, some patients remained without definitive diagnoses, and variants of uncertain significance (VUS) further complicated clinical interpretation. By clarifying the impact of genetic testing on clinical decision-making for HCTDs, our findings offer valuable insights for optimizing testing strategies, counseling, and patient management in clinical practice.