Methods

This prospective cohort study included 626 patients with HC (probands: n = 512, 82%; relatives: n = 114, 18%), who attended the cardiogenetic outpatient clinic from May 1985 to August 2014. Probands were defined as patients with HC who presented with signs or symptoms of HC. Relatives were defined as patients with HC who were identified through family screening. Each patient had an established diagnosis of HC based on maximal wall thickness (MWT) ≥15 mm unexplained by loading conditions or ≥13 mm for relatives of patients with HC. Patients with HC linked to other causes were excluded. The study conforms to the principles of the Declaration of Helsinki. All patients gave informed consent, and review board approval was obtained.

All patients underwent genetic counseling. Before the year 2012, DNA analysis consisted of direct sequencing of all coding intron-exon boundaries of the following genes: myosin binding protein C ( MYBPC3 ), myosin heavy chain 7 ( MYH7 ), regulatory myosin light chain 2 ( MYL2 ), regulatory myosin light chain 3 ( MYL3 ), troponin T ( TNNT2 ), troponin I ( TNNI3 ), cysteine and glycine-rich protein 3 ( CSRP3 ), titin-cap/telethonin ( TCAP ), α-tropomyosin 1 ( TPM1 ), cardiac muscle alpha actin ( ACTC1 ), cardiac troponin C ( TNNC1 ), and teneurin C-terminal associated peptides ( TCAP ). From 2012, next-generation-sequencing was used, covering the following genes: ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CSRP3, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR and VCL . Variants were classified into the following classes: (I) benign; (II) likely benign; (III) variant of unknown clinical significance; (IV) likely pathogenic; or (V) pathogenic, adapted from the classification proposed by Plon et al. Patients were considered G+ when the mutation was classified as class IV or V.

Follow-up data were obtained in November 2014 and were complete for 99% of patients. Mortality rate was retrieved from the civil register. An electrophysiologist evaluated implantable cardioverter defibrillator (ICD) interventions. The study end points were all-cause mortality, cardiovascular (CV) mortality, HF-related mortality, and SCD/aborted SCD. Cardiac transplantation was considered HF-related mortality. CV mortality consisted of HF-related death, SCD/aborted SCD, postoperative death after a cardiac intervention, and stroke-related death. SCD/aborted SCD was defined as: (1) instantaneous and unexpected death in patients who were previously in a stable clinical condition or nocturnal death with no history of worsening symptoms; (2) resuscitation after cardiac arrest; or (3) ICD intervention for ventricular fibrillation or for fast ventricular tachycardia (>200 beats/min). Syncope was defined according to the guidelines.

Statistical analyses were performed using SPSS 21 (IBM, Armonk, New York) and Access 2010 version 14.0.7143.5000 (Microsoft, Redmond, Washington). Unpaired t test or the chi-square test were used to compare variables. p Values <0.05 were considered significant. Multivariate analysis was performed with a model in which each variable with p <0.05 (based on univariate analysis) was entered, with a maximum of 1 variable per 10 events. Survival curves were constructed according to the Kaplan–Meier method and compared using the log-rank test. Due to a high prevalence of 3 MYBPC3 founder mutations (c.2373dupG, c.2827 C>T and c.2864_2865delCT), we adjusted for the founder effect by including only the first enrolled proband with a founder mutation. Founder mutations were defined according to Alders et al. All reported annual mortality rates are in 50-year survivors.

Results

The baseline characteristics are presented in Table 1 . A pathogenic mutation was detected in 234 probands (46%), and in 93 relatives (82%). G+ probands were younger than G− probands (46 ± 15 vs 55 ± 15 years, p <0.001), had more AF (26% vs 15%; p <0.001), and a higher MWT (20 ± 5 mm vs 18 ± 4 mm; p <0.001). The following risk factors for SCD were more common in G+ probands: family history of SCD, nonsustained ventricular tachycardia, syncope, and MWT ≥30 mm. G− probands were more symptomatic (New York Heart Association ≥II 73% vs 53%, p ≤0.001) and had higher left ventricular outflow tract (LVOT) gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). Relatives presented to clinic primarily through familial evaluation (n = 66, 58%) and through positive genetic screening (n = 48, 42%). Compared with probands, relatives were younger (46 ± 15 vs 51 ± 15 years, p = 0.003), had fewer AF (11% vs 20%, p = 0.034), were less symptomatic (New York Heart Association ≥II 18% vs 64%, p <0.001), had a lower MWT (17 ± 4 vs 19 ± 5 mm, p <0.001), smaller left atria (41 ± 7 vs 45 ± 8, p <0.001), and had lower LVOT peak gradients (11 ± 15 vs 36 ± 37, p <0.001). Relatives more often had a family history of SCD (28% vs 12%, p <0.001). There were no significant differences between G+ and G− relatives ( Table 1 ).

The distribution of the affected genes is presented in Figure 1 . Next-generation sequencing was performed in 161 patients (26%). Most patients had MYBPC3 mutations (n = 240; 73%), followed by MYH7 mutations (n = 47; 14%) and thin filament mutations (n = 19; 6%). Figure 2 demonstrates the distribution of the MYBPC3 founder mutations. MYBPC3 founder mutations were present in 101 G+ probands (47%) and 53 G+ relatives (57%). A detailed overview of the individual pathogenic mutations is presented in Supplementary Table 1 . Three patients (1%) had multiple mutations: 1 compound heterozygous MYBPC3 mutation in trans and 2 double heterozygous ( MYBPC3 / MYL2 and MYH7 / MIB1 ) mutations. Most mutations were truncating mutations (n = 184; 56%) followed by missense (n = 101; 31%) and splice site mutations (n = 34; 10%). Supplementary Table 2 illustrates the varying types of mutations in the patients who died from HF and SCD/aborted SCD. The gene most commonly affected in SCD/aborted SCD was MYBPC3 (founder: n = 10, nonfounder: n = 6), followed by MYH7 (n = 2), and a double mutation carrier. SCD/aborted SCD did not occur among TNNT2 mutation carriers (n = 10; mean age 61 ± 9).

The distribution of pathogenic gene mutations in 512 probands (A; top) and 114 relatives (B; bottom) . G− = genotype-negative HC patients. Thick = patients with thick filament–associated gene mutations: myosin binding protein C ( MYBPC3 ), myosin heavy chain 7 ( MYH7 ), regulatory myosin light chain 2 ( MYL2 ) and regulatory myosin light chain 3 ( MYL3 ). Thin = patients with thin filament–associated gene mutations: troponin I, troponin T, and α-tropomyosin 1. Rare = patients with rare mutations: calreticulin 3, cysteine and glycine-rich protein 3, and myopalladin. Multiple = patients with multiple mutations.

The distribution of founder and nonfounder mutations in the myosin binding protein C ( MYBPC3 ) gene. MYBPC3 founder mutations include: c.2373dupG (purple) ; n = 78 (33%), c.2827 C > T (green) ; n = 42 (18%); and c.2864_2865delCT (red); n = 33 (14%). Nonfounder MYBPC3 mutations (black) : n = 86 (36%).

Mortality and interventions during follow-up are presented in Table 2 . During the mean follow-up period of 12 ± 9 years, G+ probands had a greater probability of all end points: all-cause mortality, HF-related mortality, CV mortality, and SCD/aborted SCD ( Figures 3 and 4 ). Annual rates for G+ versus G− patients were as follows: (1) all-cause mortality: 2.4% versus 1.0%, log-rank p <0.001; (2) HF-related mortality: 0.9% versus 0.2%, log-rank p <0.001; (3) CV mortality: 1.8% versus 0.4%, log-rank p <0.001; and (4) SCD/aborted SCD: 1.1% versus 0.15%, log-rank p = 0.002. After adjustment for the founder effect, all these differences remained significant. ICDs for primary prevention were implanted more often in G+ probands (16% vs 9%; p = 0.019). There was no significant difference in the number of septal reduction therapies (both ASA and surgical myectomy) between G+ and G− probands (31% vs 33%; p = 0.710). All-cause mortality for relatives was comparable to probands (10% vs 14%, p = 0.247), with an annual all-cause mortality rate of 1.3%. Compared with probands, cardiovascular death trended lower in relatives (4% vs 9%, p = 0.084). There were no significant differences between G+ and G− relatives. Multivariate Cox regression analyses of G+ status in probands for the end points are presented in Table 3 . G+ status was an independent predictor of all-cause mortality (HR 1.90, p = 0.014), CV mortality (HR 2.82, p = 0.002), and HF-related mortality (HR 6.33, p = 0.004). G+ status was also a predictor of SCD/aborted SCD, after adjusting for established risk factors for SCD as described in the guidelines from 2003 and 2011.

Kaplan–Meier analysis comparing (A; top) all-cause mortality in G+ probands and G− probands and (B; bottom) cardiovascular mortality in G+ probands and G− probands. * = age at presentation ( red for G+ and black for G−). G+ = genotype-positive. G− = genotype-negative. Cardiovascular mortality is defined as death related to HF or stroke, SCD or postoperative death after a cardiac intervention.

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