Objectives To determine the prevalence and spectrum of mutations and genotype phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test. Patients and Methods Between 1999 and 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male, age at diagnosis 44.4 ± 19 years) had HCM genetic testing for the HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical record. Results Overall, 359 patients (34%) were genotype positive for a putative HCM associated mutation in ≥ 1 HCM-associated gene. Univariate and multivariate analyses demonstrated echocardiographic reverse curve morphology, age at diagnosis < 45 years, MLVWT ≥ 20 mm, family history of HCM, and family history of SCD to be positive predictors of positive genetic test while hypertension was a negative predictor. A score, based on the number 6 predictors of a positive genetic test, predicted a positive genetic test ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present. Conclusions In this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all patients were diagnosed clinically with HCM, the presence or absence of six simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing with the use of the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.

Background Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels. Methods and Results Participants (n=203, 45–65 years old, at intermediate risk for CHD, and not on statins) were randomized to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS (+GRS). Participants in the +GRS group were stratified as having high (+H-GRS) or average/low (+L-GRS) GRS. Risk was disclosed by a genetic counselor followed by shared decision-making regarding statin therapy with a physician. We compared the primary endpoint of LDL-C levels at 6 months and assessed whether any differences were due to changes in dietary fat intake, physical activity levels or statin use. Participants (mean age 59.4±5 years, 48% men, mean 10-year CHD risk 8.5±4.1%) were allocated to receive either CRS (n=100) or +GRS (n=103). At the end of the study period, the +GRS group had a lower LDL-C than the CRS group (96.5±32.7 vs. 105.9±33.3 mg/dL; P=0.04). +H-GRS participants had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not +L-GRS participants (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the +GRS group than in the CRS group (39% vs. 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted. Conclusions Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone. Clinical Trial Registration Information ClinicalTrials.gov. Identifier: NCT01936675.

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