Novel genotype–phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy

Abstract

ObjectiveA predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype.MethodsUnrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival.Results874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values<0.0005) and an increased incidence of cardiovascular death (p=0.012). Similar associations were observed for individual SP genes. Patients with ANK2 variants had greater maximum wall thickness (p=0.0005). Associations at a lower level of significance were demonstrated with variation in other non-SP genes.ConclusionsPatients with HCM caused by rare SP variants differ with respect to age at presentation, family history of the disease, morphology and survival from patients without SP variants. Novel associations for SP genes are reported and, for the first time, we demonstrate possible influence of variation in non-SP genes associated with other forms of cardiomyopathy and arrhythmia syndromes on the clinical phenotype of HCM.

Founder Mutations in Myosin-Binding Protein C

“…This is consistent with a growing body of evidence that supports a lower risk profile among genotype-negative HCM, with lower rates of cardiovascular mortality, heart failure-related mortality, and SCD/aborted SCD compared with genotype-positive HCM. 14,[16][17][18] These data collectively support the concept that genotype-negative, nonfamilial HCM represents a clinically distinct disease process, perhaps elicited by a combination of multiple genetic variants of low effect size, lifestyle factors (eg, hypertension), and age, rather than being caused by single autosomal-dominant mutations with strong independent effects. This concept is supported by a recent study where HCM was diagnosed in only 3% of first-degree relatives of HCM probands in the absence of a sarcomere gene mutation or family history of HCM, with none of these individuals reporting adverse events.…”

“…In fact, FG+ probands had higher all-cause mortality compared with nonfounder G+ probands (29% versus 15%; P<0.05 in Table 3), although with Kaplan-Meier analysis, this comparison did not reach statistical significance (P=0.14). The progression to systolic dysfunction (defined as ejection fraction <55%) in the FG+ probands and nonfounder G+ probands was high compared with previously published cohorts 14,15 but similar between groups (46% for each). One potential reason for this may be a higher cutoff for low ejection fraction (most prior studies use 50%), although arguably 55% is probably more appropriate given the typical hyperdynamic HCM phenotype.…”

Relationship between aetiology and left ventricular systolic dysfunction in hypertrophic cardiomyopathy

“…The Heart Hospital population comprised a cohort of unrelated consecutive patients with idiopathic or sarcomeric HCM who were tested for sarcomeric protein gene mutations using high-throughput sequencing between 2011 and 201315 and all patients diagnosed with one of the following conditions between 1991 and 2014: Anderson-Fabry disease (AFD); primary mitochondrial disease; immunoglobulin light chain amyloidosis (AL); hereditary transthyretin type amyloidosis; wild-type or senile systemic amyloidosis (SSA); Noonan syndrome; Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, Deafness (LEOPARD) syndrome; carnitine palmitoyltransferase II (CPT II) deficiency; mutations in the four-and-a-half LIM domain protein 1 (FHL1) gene; Friedreich's ataxia and glycogen storage disease (GSD) including Danon disease and AMP-protein kinase deficiency caused by mutations in PRKAG2.…”

Cardiopulmonary exercise test and sudden cardiac death risk in hypertrophic cardiomyopathy

“…Nonetheless, it should be underlined that the sensitivity and specificity of the VE/VCO 2 slope cut-off point derived in the same data where it is being tested in will naturally have superior performance compared with externally derived metrics. The lack of data on cardiac resonance imaging as well as the fact that a possible impact of different gene mutations has not been investigated represent obvious limitations 33 34. Furthermore, we acknowledge that our SCD risk analysis considered syncopal episodes occurred ≤5 years instead of <1 year 5.…”