Diagnostic Accuracy of Clinical Manifestations in Identifying People With Tuberous Sclerosis Complex.

Background and Objectives: Up to 10%-15% of people with tuberous sclerosis complex (PwTSC) do not carry an identifiable pathogenic variant in Methods: We used the TSC Natural History Database, a longitudinal database of PwTSC from 22 North American centers. We used a definite genetic TSC diagnosis as our gold standard. We estimated the sensitivity (95% CI) of TSC-related skin, structural brain, renal, and cardiac manifestations, as well as combinations of these manifestations. Using a series of sensitivity analyses to test alternate assumptions, we estimated positive predictive values and negative predictive values (PPVs and NPVs). Results: Among the 1,300 genetics-positive PwTSC, 50.3% were female and the mean age at diagnosis was 3.7 years. The sensitivity of at least one skin or structural brain manifestation was 98.7% (95% CI 98.0-99.2). The PPV and NPV were 83.2 (95% CI 81.6-84.6) and 98.4% (95% CI 97.8-98.8), respectively, while assuming 50% prevalence and 80% specificity. Including cardiac manifestations marginally increased the sensitivity, PPV, and NPV to 99.5% (95% CI 98.9-99.7), 83.3% (95% CI 81.8-84.7), and 99.4% (95% CI 99.0-99.6), respectively. Other combinations of TSC manifestations had lower or similar diagnostic accuracy. Discussion: Assessment of brain and skin manifestations in family members of genetics-positive PwTSC is sufficient to screen for TSC in most cases, with excellent sensitivity and NPV. Our findings are potentially applicable to family members of genetics-negative PwTSC. Further cardiac screening may optimize diagnostic accuracy in selected cases. Classification of Evidence: This study provides Class IV evidence that a combination of brain and skin manifestations is highly sensitive for diagnosing TSC in family members of patients with genetically confirmed TSC.