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 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.

Distinguishing ventricular septal bulge versus hypertrophic cardiomyopathy in the elderly

“…Patients with VSB did not display a sex preference,1 14 15 in contrast to HCM, which has been generally characterised by a 3:2 male predominance,6 at least at younger ages 20 21. A recent review of 969 consecutive American and Italian patients with HCM demonstrated a reversed 60% versus 30% female predominance only in patients older than 60 years of age 22.…”

“…Thus, a history of hypertension can no longer be considered tout court as an exclusion criterion for HCM when dealing with elderly patients. Indeed, in contemporary adult HCM populations, prevalence of hypertension ranges from 20% to 60% 20 21 23 25–29. The prevalence of hypertension in VSB observational studies ranges between 50% and 80%,1 14 15 thus slightly higher than that reported in HCM studies.…”

“…Some Authors included subjects with sigmoid-shaped septum without hypertrophy,15 but most VSB cohorts comprised only individuals with a proximal septal wall thickness >12–13 mm,1 2 13 14 16 applying the same entry criterion used in contemporary HCM cohorts 20 21. Thus, a considerable overlap exists between the two conditions.…”

“…Although several commercial genetic panels are available, the clinical use of genetic testing is limited, because of the vast genetic heterogeneity and the lack of association between prognosis and specific mutations. Among those tested, approximately 35% is found to be positive for a known gene 20 21. Yield of genetic testing is even lower in elderly patients with HCM, and approaches 10% in those with sigmoidal HCM (figure 2).…”

The 25-Year Genetic Era in Hypertrophic Cardiomyopathy: Revisited

“…These findings are novel and informative by providing a reliable number (ie, 35%) 7 for the true yield and proportion of families that will have access to generational genetic screening should they choose this strategy over (or following) clinical screening with echocardiography and cardiovascular magnetic resonance (CMR) imaging. 4,8 This is a particularly important observation because too often the likelihood of successful genetic family screening has been cited as 50% to 70%, 1,2 a figure that includes variants of uncertain significance, which are usually sarcomere mutations not yet regarded as disease causing.…”