41 Predictably positive? An evaluation on genotype predictor clinical tools in a specialised inherited cardiac condition centre

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Background Genetic testing is increasingly utilised in the investigation and management of patients with inherited cardiac conditions (ICCs). This study evaluates the efficacy of genotype predictor clinical tools for three ICCs; the Mayo score (MS) for hypertrophic cardiomyopathy (HCM), the Madrid DCM score for dilated cardiomyopathy (DCM), and the Schwartz score (SS) for long QT syndrome (LQTS). Methods A retrospective service evaluation was conducted on genetic tests from a single centre for ICCs in 2022. The cohort included patients undergoing diagnostic genetic testing for HCM, DCM, and LQTS. Pathogenic/likely pathogenic genetic variations (G+), variations of uncertain significance (VUS) and no pathogenic genetic variations (G-) were identified. Predictive scoring tools were applied to each condition to assess the predictive efficacy of each tool. Results 91 genetic tests were conducted on patients with suspected ICCs, comprising of 46 HCM, 22 DCM, and 23 LQTS patients. Of these, 25 tests were G+, 9 were VUS and 57 were G-. The application of the MS for HCM revealed a distinct pattern. For G- patients, mean MS was 1.75, with a median of 3 and mode of 0. These findings align with expected likelihood of obtaining a G- result based on MS. However, in G+ patients, mean MS increased to 2.46, with a median and mode of 3. (Figure 1) Although the mean is marginally higher than the comparator, MS exhibited variability in the G+ group, and higher scores were not consistently observed in every G+ case. Similarly for LQTS, the G- group had a mean SS of 1.18, a median of 1.14 and a mode of 1. These findings are consistent with the rationale that lower SS are less likely to be associated with a true genetic cause for LQTS. Conversely, the G+ group displayed a significantly higher mean SS of 3.28, with a median and mode of 4. (Figure 2) Finally, in DCM the Madrid scoring for G+ group displayed a mean of 43.34%, with median and mode of 36.55%. In contrast, the G- group had a marginally lower mean of 27.26%, a median of 36.34% and mode of 6.57%. This predictive score was less specific, and displayed wide variability between positive and negative results. Conclusion The application of predictive scoring tools for each condition varied in their effectiveness. Lower values in the MS and SS were largely consistent with G- results. However, MS exhibited variability in G+ results, potentially limiting its utility in predicting G+ results in HCM. In contrast, SS proved more accurate in predicting G+ results, thus enhancing its clinical relevance in detecting genetic aetiology for LQTS. The Madrid score demonstrated wide variation in scores for both G+ and G- results, indicating limited usefulness in clinical practice for DCM . This study reinforces the importance of clinical correlation on a case by case basis. Further studies are warranted to comprehensively evaluate the specificity and sensitivity of these clinical tools, to ultimately determine their utility in practice.

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