Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

Background

The American College of Cardiology (ACC)/American Heart Association (AHA) recommend screening for family members of first-degree relatives of affected probands with hypertrophic cardiomyopathy (HCM) at 12 years, or earlier in cases with an early growth spurt, family history of sudden cardiac death (SCD), and prior to competitive sports participation.

The European Society of Cardiology (ESC) recommends that clinical and/or genetic screening be offered from age 10 years onwards, with earlier screening to be considered in families with malignant early onset disease, presence of cardiac symptoms or are involvement in demanding physical activity.

The primary goal of this study was to evaluate if the current screening guidelines miss early onset disease which can impact timely interventions aimed at preventing adverse outcomes.

Methods

A single center, retrospective cohort study of children who underwent screening in a single teritary center between 2000 and 2018.

The screening visit included an electrocardiogram (ECG), an echocardiography and genetic counselling for the purpose of cascade genetic testing, prior to 18 years of age as part of family screening for primary HCM.

First-degree relatives of HCM probands were screened clinically independent of age, although echocardiography was sometimes delayed till 3 years of age to avoid sedation for echocardiography. Hypertrophic cardiomyopathy probands and families with secondary HCM (e.g. syndromic, neuromuscular, metabolic, or mitochondrial disease) were excluded.

Results

A total of 331 individuals were screened before 10 years of age, 52 (9.9%) were phenotype-positive at first evaluation and an additional 28 (5.4%) became phenotype-positive during follow-up. Only 6 (1.1%) children were symptomatic at first screening.

About 198 (37.8%) had a positive family history of SCD.

Of the 120 children from genotype-positive families who had clinical genetic testing, 86 (71.7%) were genotype-positive, with variants in MYH7 and MYBPC3 accounted for over 60% of genotype-positive cases.

The median age at onset of HCM was 8.9 (4.7–13.4) years. Freedom from phenotype-positive HCM at 10 years of age was 91.0%. Of the 80 phenotype-positive children, 42 (52.5%) became phenotype-positive before 10 years of age (Figure 2A).

Of the 17 children of MaCE during follow-up, 7 occurred before 10 years of age. With 2206 patient-years of follow-up, incidence rate of MaCE was 0.95 per 100 patient-years. All events occurred in phenotype-positive children, and 13 of these children had early onset HCM.

Overall, 201 (38.4%) children fulfilled criteria for early screening based on symptoms or family history of SCD. However, among the 42 children with HCM before 10 years of age, only 29 (69%) met criteria for early screening. Freedom from HCM at 10 years of age was 84.3% in subjects eligible for early screening compared to 94.9% in subjects not (P = 0.0003).

On multivariable Cox regression, male gender, family history of SCD/ICD, and P/LP variant in MYH7 or MYBPC3 in the child or family were associated with early onset HCM.

Family history of SCD prior to 25 years of age, symptoms at screening and presence of a P/LP MYH7 or MYBPC3 variant were associated with early occurrence of a MaCE.

In adjusted models for either outcomes of freedom from early onset HCM and freedom from early MaCEs, the combined clinical and genetic model performed better than the model with only clinical factors.

Discussion

9.9% children screened for HCM were already phenotype-positive at first evaluation with MaCEs occurrence at a median follow-up of 1.5 (0.5–4.1) years from onset of HCM. This suggests that many children already had a well-established phenotype by the time they were screened with a relatively rapid progression on follow-up.

A third of early HCM cases did not fulfil criteria for early screening like symptoms or family history of SCD. 31% children with early onset HCM did not meet eligibility for early screening and would potentially have been missed.

Male gender, family history of SCD and presence of P/LP variants in MYH7 or MYBPC3 were predictors of early onset HCM and of MaCEs. Event rates in phenotype-positive children are not different than in adults.

This study along with other recent reports (Norrish et al, 2019) suggest that disease prevalence in children and pre-adolescents is not lower than in adolescents. Other publications report that genotype-positive individuals who remain phenotype-negative by 18 years have a low frequency (10%) of phenotype conversion. Together, this suggests that disease prevalence and penetrance in children is not lower than in adolescents or even adults (Maurizi et al, 2019).

Despite good discriminative ability, the combined clinical and genetic models were not perfect, and this may be related to partial availability of genetic information. This suggests that until better validated prediction models of early onset disease are available, clinical and genetic screening should not be delayed until 10 or 12 years of age since studies report effective coping with a positive result and no difference in quality of life between gene-positive children and peers (Meulenkamp et al, 2008 and Smets et al, 2008).