Abstract 15017: Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients with Hypertrophic Cardiomyopathy
Background. Hypertrophic cardiomyopathy (HCM) is a disease of profound phenotypic and genotypic heterogeneity and the most common cause of sudden cardiac death (SCD) in young adults. Commercial genetic testing is currently available. However, the yield of genetic testing varies widely between cohorts. Herein, we present a phenotype-derived score to provide physicians with a pre-test probability for a positive HCM genetic test.
Methods. Between 1999 and 2007, 1060 unrelated patients with the clinical diagnosis of HCM (60% male, age at diagnosis 44.4 ± 19 years) were enrolled for research-based genetic testing (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNT2, TNNI3, TPM1) that encode the critical myofilament/sarcomeric proteins and causing HCM. Comprehensive phenotyping was done by review of electronic medical records and used for genotype-phenotype analyses. Yield of genetic testing was determined using t-test, univariate, multivariate, and ROC analyses.
Results. Overall, 399 patients (38%) were genotype positive for a putative HCM-associated mutation in >1 HCM-associated gene. ROC analyses demonstrated the cut-off for a positive genetic test for age at diagnosis at 45.2 years (area under curve 0.69, sensitivity 71%, specificity 61%) and maximum left ventricular wall thickness (MLVWT) at 21 mm (area under curve 0.63, sensitivity 54%, specificity 67%). Univariate and multivariate analyses showed echocardiographic reverse curve morphology, age at diagnosis ≤45 years, MLVWT≥21 mm, family history of HCM or SCD were predictors of positive genetic test with highest odds ratio (OR) for reverse curve morphology (OR 3.7, p<0.001) and family history of HCM (OR 2.3; p<0.001). Counting the presence of each of 5 risk factors (RF), the likelihood of a positive genetic test result increased with the number of RFs: 13% for 0 RF, 23% for 1 RF, 43% for 2 RFs, 59% for 3 RFs, and 74% for ≥ 4 RFs (p < 0.001).
Conclusions. In this largest HCM cohort published to date, the overall yield of genetic testing was <40%. Although all were diagnosed clinically with HCM, the presence or absence of 5 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive, sarcomeric HCM with <15% chance when all 5 markers were absent to ~75% chance in the presence of ≥4 markers.
- © 2012 by American Heart Association, Inc.