Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

BACKGROUND Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. OBJECTIVES The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers. METHODS This was a retrospective analysis of adult and pediatric SP mutation carriers identi ﬁ ed during family screening who did not ful ﬁ ll diagnostic criteria for HCM at ﬁ rst evaluation. RESULTS The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n ¼ 123 (43.2%), MYH7 n ¼ 69 (24.2%), TNNI3 n ¼ 39 (13.7%), TNNT2 n ¼ 34 (11.9%), TPM1 n ¼ 9 (3.2%), MYL2 n ¼ 6 (2.1%), ACTC1 n ¼ 1 (0.4%), multiple mutations n ¼ 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) ful ﬁ lled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up

P rovision of genetic testing to the relatives of patients with hypertrophic cardiomyopathy (HCM) caused by pathogenic/likely pathogenic (P/LP) variants in sarcomere protein (SP) genes is standard of care in clinical practice guidelines (1).
Adoption of this recommendation has led to the identification of a growing number of individuals that carry SP gene P/LP variants in the absence of an overt cardiomyopathy on cardiac imaging who are offered lifelong follow-up. The evidence to support this strategy is, however, relatively weak (2)(3)(4)(5)(6)(7)(8), as most studies are limited by small cohort size, restriction to children (2,3), and the influence of founder SP gene variants (7,8). Ongoing screening of healthy SP P/LP variant carriers also poses a potentially unsustainable burden on health care providers and relatives alike.
The primary aim of this study was to determine the incidence of a new HCM diagnosis in relatives with SP P/LP variants and to evaluate predictors of phenotype development. The secondary aim was to assess the incidence of major cardiovascular events in relatives carrying SP P/LP variants. All underwent standard electrocardiography (ECG) and 2-dimensional echocardiography at 1 to 3 yearly intervals and cardiac magnetic resonance (CMR) imaging at physician's discretion as previously described (9). The study conforms to the declaration of Helsinki (10) and the retrospective data collection was approved by the local ethics committee (reference 19/WS/0100).
GENETICS. All SP variants were reviewed and classified in January 2020 according to the American College of Medical Genetics and Genomics criteria (11) Children: LV wall thickness more than 2 standard deviations (SDs) greater than the predicted mean (z-score >2).    groups differed by genotype, sex, and age, with a higher male prevalence among those who developed overt HCM, and younger age in individuals with only an abnormal ECG compared with those with a normal phenotype and those with overt HCM ( Table 1).
Supplemental Figure 2 shows the phenotype at the end of follow-up according to age.
Supplemental Table 2 reports the characteristics of the study cohort by age at first evaluation; penetrance was similar in the pediatric and adult subgroups ( Figure 2C).  Figure 1). An abnormal ECG was a strong risk factor for a subsequent diagnosis of HCM ( Figure 2B).
Overall, 145 subjects (50.9%) underwent a CMR with no clear difference between those who developed HCM and those who did not ( Table 1). Among those diagnosed with HCM who underwent CMR, 16 (32.0%) of 50 fulfilled criteria on CMR but not echocardiography; 50% of these individuals (n ¼ 8) had a normal ECG at the time of HCM diagnosis (Figure 3).

Penetrance in Sarcomere Mutation Carriers
A U G U S T 4 , 2 0 2 0 : 5 5 0 -9 penetrance of HCM. Older age at first evaluation was also associated with an increased risk ( Table 3).    After adjusting for baseline differences (including genotype), imaging technique, and age, we found the risk of developing HCM to be 3 times higher in male individuals. This remains unexplained, as does the higher mortality that has been observed in female individuals in large HCM cohorts in spite of this male predominance (18)(19)(20).
An abnormal ECG was strongly associated with the subsequent development of HCM ( Figure 2B) and was independent of genotype and sex. This confirms the important role of the ECG as a screening tool as well as the need for long-term surveillance in individuals with an abnormal ECG. However, a normal ECG did

HCM Penetrance
Penetrance is lowest in subjects with TNNI3 variants, compared to MYBPC3, MYH7, and TNNT2 (A), was similar in adult and pediatric subjects (C), and an abnormal ECG was a strong predictor of subsequently developing overt HCM (B). Abbreviations as in Figure 1.  This is the first large study on disease penetrance in SP carriers to compare echocardiography with CMR. CMR was not clearly associated with a more frequent diagnosis of HCM during follow-up, but a subset of patients fulfilled diagnostic criteria on CMR but not on echocardiography. This may be explained by suboptimal echocardiographic imaging, particularly in regions of the LV that are more challenging to image, for example, the basal anterior and anterolateral wall (22). It is noteworthy that a small number of cases who fulfilled diagnostic criteria on CMR but not on echocardiography also had a normal ECG ( Figure 3).
The growing number of healthy SP P/LP variant carriers is one of the greatest logistical problems facing clinical services dedicated to the evaluation of families with HCM, but the optimal timing and interval of screening is still debated (23)(24)(25). This study supports the need for lifelong surveillance that should commence at a younger age than currently recommended by the major societies in Europe and North America (1,24). Our data also suggest that, following an initial negative screening visit, the timing of follow-up should not be tailored to age, but rather to sex, ECG findings, and causal gene.
Although larger prospective studies are needed to confirm our findings and establish the optimal timing of cardiac imaging, following the documentation of P/ LP variant carrier status, CMR should be considered at baseline in adults, adolescents, and children old enough to undergo CMR without general anesthesia.
Although our data suggest that regular CMR scans also should be considered during follow-up, in the absence of a standardized protocol in this study, the optimal interval for repeat CMR cannot be estab- Selection bias toward individuals with higher disease penetrance cannot be excluded because families  Table 1.