Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy

Abstract

Objectives: To determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result.

Patients and methods: Between April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4 ± 19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records.

Results: Overall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present.

Conclusion: In this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.

Figure 1. Genotype-phenotype analyses for patients with 1 or > 1 mutation

Genotype-phenotype analyses for patients with 1 (n = 341) or > 1 mutation (n = 18) with respect to age at diagnosis (top left), maximum left ventricular wall thickness (MLVWT) (top right), family history of HCM (bottom left), and family history of SCD (bottom right). A p-value for the overall analysis is shown in the black box. P-values for analyses between each subgroup are shown above black bars.

Figure 2. ROC-analyses

Receiver-operator characteristic (ROC) analyses for continuous variables (age at diagnosis; left, and maximum left ventricular wall thickness (right) determining the cut-off for a positive genetic test.

Figure 3. Mayo HCM Genotype Predictor Score

Figure showing the components of the Mayo HCM Predictor Score and points attributed to each marker on the right. Bar diagram (right) showing the yield of genetic testing for each of the scored subgroups predicting a positive genetic test from 6% to over 80%.