Author + information
- Received November 22, 2017
- Accepted December 8, 2017
- Published online February 12, 2018.
- Jaap I. van Waning, MDa,
- Kadir Caliskan, MD, PhDb,
- Yvonne M. Hoedemaekers, MD, PhDc,
- Karin Y. van Spaendonck-Zwarts, MD, PhDd,
- Annette F. Baas, MD, PhDe,
- S. Matthijs Boekholdt, MD, PhDf,
- Joost P. van Melle, MDg,
- Arco J. Teske, MD, PhDh,
- Folkert W. Asselbergs, MD, PhDh,
- Ad P.C.M. Backx, MDi,
- Gideon J. du Marchie Sarvaas, MDj,
- Michiel Dalinghaus, MD, PhDk,
- Johannes M.P.J. Breur, MD, PhDl,
- Marijke P.M. Linschoten, MsCh,
- Laura A. Verlooij, MDc,
- Isabella Kardys, MD, PhDb,
- Dennis Dooijes, PhDe,
- Ronald H. Lekanne Deprez, PhDd,
- Arne S. IJpma, PhDa,
- Maarten P. van den Berg, MD, PhDg,
- Robert M.W. Hofstra, PhDa,
- Marjon A. van Slegtenhorst, PhDa,
- Jan D.H. Jongbloed, PhDc and
- Danielle Majoor-Krakauer, MD, PhDa,∗ ()
- aDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
- bDepartment of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
- cDepartment of Clinical Genetics, University Medical Center Groningen, Groningen, the Netherlands
- dDepartment of Clinical Genetics, Amsterdam Medical Center, Amsterdam, the Netherlands
- eDepartment of Clinical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- fDepartment of Cardiology, Amsterdam Medical Center, Amsterdam, the Netherlands
- gDepartment of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
- hDepartment of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
- iDepartment of Pediatrics, Amsterdam Medical Center, Amsterdam, the Netherlands
- jDepartment of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands
- kDepartment of Pediatrics, Erasmus Medical Center, Rotterdam, the Netherlands
- lDepartment of Pediatrics, University Medical Center, Utrecht, the Netherlands
- ↵∗Address for correspondence:
Dr. Danielle Majoor-Krakauer, Department of Clinical Genetics, EE 2036, Erasmus Medical Center, PO Box 2040, 3000CA Rotterdam, the Netherlands.
Background The clinical outcomes of noncompaction cardiomyopathy (NCCM) range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death. Genetics play an important role in NCCM.
Objectives This study investigated the correlations among genetics, clinical features, and outcomes in adults and children diagnosed with NCCM.
Methods A retrospective multicenter study from 4 cardiogenetic centers in the Netherlands classified 327 unrelated NCCM patients into 3 categories: 1) genetic, with a mutation in 32% (81 adults; 23 children) of patients; 2) probably genetic, familial cardiomyopathy without a mutation in 16% (45 adults; 8 children) of patients; or 3) sporadic, no family history, without mutation in 52% (149 adults; 21 children) of patients. Clinical features and major adverse cardiac events (MACE) during follow-up were compared across the children and adults.
Results MYH7, MYBPC3, and TTN mutations were the most common mutations (71%) found in genetic NCCM. The risk of having reduced left ventricular (LV) systolic dysfunction was higher for genetic patients compared with the probably genetic and sporadic cases (p = 0.024), with the highest risk in patients with multiple mutations and TTN mutations. Mutations were more frequent in children (p = 0.04) and were associated with MACE (p = 0.025). Adults were more likely to have sporadic NCCM. High risk for cardiac events in children and adults was related to LV systolic dysfunction in mutation carriers, but not in sporadic cases. Patients with MYH7 mutations had low risk for MACE (p = 0.03).
Conclusions NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status.
Noncompaction cardiomyopathy (NCCM), which is also known as left ventricular (LV) noncompaction, is a cardiomyopathy with excessive trabeculations of the LV, with a >2-fold thickening of the endocardial noncompacted layer compared with the epicardial compacted layer of the myocardium (NC/C >2) (1–3). Initially referred to as “spongy” heart, NCCM has gained attention because of improvements in cardiac imaging that allow more detailed visualization and increased clinical awareness of this syndrome (4,5). Clinical symptoms range from severe prenatal manifestations to asymptomatic cardiomyopathy presenting in adults (6,7).
Genetics play an important role in NCCM because 17% to 50% (8,9) of patients have a family member with cardiomyopathy, and the yield of DNA testing ranges from 17% to 41% depending on patient selection and the number of genes screened (10,11). In most families, an autosomal dominant pattern of inheritance is observed with variable penetrance (12). Most of the genetic defects associated with NCCM have also been reported in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (10,13). In NCCM, mutations in the sarcomere genes, particular in MYH7, are the most common (10,11). However, the role of the sarcomere gene defects in the development of cardiac hypertrabeculation has not been established yet. The diagnosis of NCCM requires genetic counseling because timely screening and diagnosis of at-risk relatives is important. Finding a mutation allows prediction to identify accurately the relatives at risk for NCCM. Because NCCM is not as common as HCM and DCM, associations among mutations in cardiomyopathy genes, family history and the age of onset, LV systolic dysfunction, and long-term outcome have not been previously investigated in detail.
We conducted a large multicenter study in 4 cardiogenetic centers in the Netherlands to investigate the role of genetics in NCCM. The focus of the study was to investigate the relationship between clinical and cardiologic features at diagnosis, the risk of LV systolic dysfunction, and the occurrence of major adverse cardiac events (MACE) during follow-up in NCCM patients diagnosed in childhood or adulthood. These insights may help to improve management of NCCM patients and their families.
The retrospective study consisted of 327 unrelated NCCM patients referred to 1 of the participating departments of Clinical Genetics for genetic counseling and DNA testing (with informed consent) between January 2005 and January 2016. Sixteen patients who did not have DNA testing were excluded (Online Appendix). Diagnosis of NCCM was based on consensus of re-evaluated echocardiography and magnetic resonance imaging (MRI), according to the Jenni and Petersen criteria by J. van Waning and a dedicated participating cardiologist (3,5). Echocardiographic and MRI data were available for all patients, except for 34 patients with only MRI and 80 patients with only echocardiographic data. One patient was diagnosed at autopsy.
Specifics on the genes tested and methods of classification of variants are described in detail in the Online Methods. The core panel of tested cardiomyopathy genes included 45 cardiomyopathy genes. All variants were evaluated according to the current Dutch guidelines, and classification of each variant was achieved with consensus of the participating molecular geneticists. Patients were classified as genetic if they had a (likely) pathogenic mutation (Online Tables 1 and 2). Variants of unknown clinical significance (VUS) are reported in Online Table 3. Patients with only a VUS were not classified as genetic because these variants were not proven to be pathogenic. Patients were classified as probably genetic if they had a family history of cardiomyopathy and if DNA testing did not identify a mutation. Patients were classified as sporadic if patients had no mutation or family history of cardiomyopathy (Figure 1).
Clinical data were retrieved retrospectively from the medical records, including age, sex, cardiac diagnosis, electrocardiography, echocardiography, and cardiac MRI when available. If the images of the first echocardiographic examination were unavailable, more recent echocardiographic imaging was used.
LV systolic dysfunction was defined as LV ejection fraction of <45% on MRI or fractional shortening of <19% in men and of <21% in women on echocardiography if MRI images (n = 80) were missing (14). Abnormal right ventricular (RV) systolic function was defined as a tricuspid annular plane systolic excursion <17 mm on echo or RV ejection fraction <45% on MRI (15). For children, dimensions of the ventricles of <2 SDs from the reference range were classified as abnormal (16,17).
Information on the occurrence of clinical events at follow-up was collected from the medical records. Heart failure that required hospitalization was defined as new-onset or worsening signs of heart failure that required therapy and hospitalization. Sustained ventricular tachycardia/ventricular fibrillation was identified when at least 30 s of hemodynamically stable ventricular tachycardia or hemodynamically unstable ventricular tachycardia/ventricular fibrillation of any duration was documented by electrocardiograms, pacemaker, or defibrillator data. We used a combined endpoint for our hazard models because of the low incidence of death. The occurrence of cardiac death, implantation of a LV assistance device, heart transplantation, (aborted) sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, or ischemic stroke were classified as MACE. Seventeen patients were lost to follow-up. Information on vital status was confirmed by checking municipal registries for all patients.
Family histories were ascertained at the Departments of Clinical Genetics. Patients were classified as familial, if at least 1 first-degree or 2 second-degree relatives were reported to have cardiomyopathy. None of the patients had only 1 affected second-degree relative. Medical records confirmed the diagnosis of 82% of the relatives reported to have cardiomyopathy; no medical records were available for 18% of the affected relatives. The occurrence of (aborted) sudden cardiac death at age younger than 50 years in the family of the index patients was recorded. In families with multiple cases of NCCM, only 1 case per family, the first diagnosed, was included in the study.
Categorical data were compared with Pearson’s chi-square test or Fisher exact test. For continuous variables, unpaired Student's t-tests were used for 2 groups and analysis of variance tests for >2 groups. Logistic regression was used to find associations between genetic status and LV dysfunction at baseline. Kaplan-Meier survival curves were estimated and differences between groups were assessed by the log-rank test, using time at diagnosis as time zero. Risk factors for MACE were calculated by Cox proportional hazards regression analysis. Patients lost to follow-up were considered at risk until the date of last contact, at which time point they were censored. Analysis was performed with SPSS statistical software version 21.0 (IBM, Armonk, New York).
The 327 NCCM patients were categorized into the 3 groups: 104 genetic (32%; 81 adults, 23 children); 53 probably genetic (16%; 45 adults, 8 children); and 164 sporadic (52%; 149 adults, 21 children) (Table 1, Figure 2). The complete list of mutations in children and adult NCCM patients with reference to previous reported variants, the reported cardiomyopathy (NCCM, HCM, or DCM), and the yield per tested gene are presented in the Online Tables 1a and 2a, Online Figure 1). In addition, 192 VUS in cardiomyopathy genes were identified in 111 patients (Online Table 3); 13 (12%) patients with a mutation had an additional VUS. Of the patients without a mutation, 98 (30%) had a VUS. Seventy-one (41%) of the sporadic cases had a VUS, compared with 63% of the probably genetic cases (n = 27, p = 0.013).
Of the 104 genetic cases, 82% involved a sarcomere gene (Figure 2), most (71%) had a mutation in MYH7, MYBPC3, or TTN, and 11% had a mutation in ACTC1, ACTN2, MYL2, TNNC1, TNNT2, or TPM1. Mutations were more frequent in children (44%) than in adults (30%; p = 0.036) (Table 1). MYH7 was the most frequently mutated gene in 19% (n = 10) of children and 11% (n = 29) of adults. TTN occurred frequently in adults (7%, n = 18), but not in children. Non-sarcomere gene mutations were detected in DES, DSP, FKTN, HCN4, KCNQ1, LAMP2, LMNA, MIB1, NOTCH1, PLN, RYR2, SCN5A, and TAZ. One patient classified as genetic had a 1p36 deletion. Mutations occurred more frequently in female patients irrespective of age at diagnosis (males: 27% vs. females: 38%; p = 0.039). The yield per tested gene was highest for MYH7 (13%), TTN (11%), and MYBPC3 (5%).
Complex genotypes (multiple mutations in 1 patient) in cardiomyopathy genes were more prevalent in children (10%) than in adults (3%) (p = 0.038) (Table 1, Online Tables 1b and 2b). Three children with complex MYBPC3 mutations presented with severe clinical phenotypes. Complex MYBPC3 genotypes were not observed in adults. Four adult patients had the same 2 MYH7 mutation in cis (c.1633G>A and c.2863G>A) that were not considered to be complex genotypes, and were expected to have a common ancestor. Three adult patients had the combination of a MIB1 and a TTN mutation. One patient had 3 pathogenic mutations in 3 different genes: FKTN, RBM20, and HCN4. This 53-year-old patient was first admitted to the hospital for bradycardia. He had no structural heart defects and experienced serious adverse effects at end of follow-up (at 58 years).
De novo mutations
De novo mutations involving DES and PLN were observed in 2 children, and de novo mutations involving PRDM16 and MYH7 were found in 2 adult patients. The children had severe heart failure and had a heart transplantation at a young age (the DES patient at the age of 10 years, the PLN patient at age 17 years). In contrast, the adult patients with a de novo mutation had a mild course of the disease without severe complications.
Twenty-one (40%) of the children had a family history of cardiomyopathy, as well as 36% (n = 99) of the adults (Table 1). Of the 120 familial cases, 56% (n = 67) had a (likely) pathogenic mutation. Of the 207 patients without a family history of cardiomyopathy, 18% (n = 37) had a mutation (p < 0.001). Overall, NCCM occurred in 23% (n = 76) of the affected relatives, in 12% (n = 39) of the families DCM was reported, in 3% (n = 11) HCM occurred in relatives, and in 1 family, a relative was diagnosed with arrhythmogenic cardiomyopathy. Sudden death at age younger than 50 years of a relative was reported by 7% (n = 23) of the patients, in 8% (n = 21) of the families of adult index cases, and in 4% (n = 2) of the families of pediatric index cases.
Age at diagnosis
The study population included 16% (n = 52) pediatric patients who were diagnosed at younger than 18 years of age, and 84% (n = 275) adult patients (Figure 3); the median age at diagnosis of NCCM was 41 years (range: 0 to 79 years; interquartile range [IQR]: 27 to 54 years), 44 years (range: 18 to 79 years: IQR: 33 to 56 years) for adult patients, and 8 years (range: 0 to 17 years; IQR: 0 to 14 years) for children (Table 1). Sixteen (30%) of the children were diagnosed at younger than 1 year of age. Age at diagnosis was inversely associated with the probability of finding a mutation (odds ratio: 0.983 per year; 95% confidence interval [CI]: 0.97 to 0.99; p = 0.01).
Congenital heart defect
Congenital heart defect (CHD) was observed in 9% of the patients (n = 28). In particular, children (p = 0.027) (Table 1) had more atrial septal defects (ASD) (p = 0.005) and ventricular septal defects (VSD) (p < 0.001). Six of the 16 patients diagnosed at younger than 1 year of age had a CHD. Two children and 2 adults had Ebstein anomaly and an MYH7 mutation (Central Illustration). Familial segregation of NCCM and Ebstein anomaly was observed in 1 family. MYH7 was the only sarcomere gene associated with CHD. Two children with a CHD had a chromosomal defect: 1 with a 1p36 deletion had ASD, multiple VSDs, and an open ductus arteriosus; and a trisomy-21 patient with a MYH7 mutation had ASD and VSD. The other CHDs were observed in patients with defects in nonsarcomere genes, in the probably genetic and the sporadic cases.
Eighty-three percent of the children and 85% of the adults were symptomatic at presentation. Heart failure (27%) and arrhythmias (26%) were the most common presentations in children and adults (Online Figure 2). In 4% (n = 14), the primary presentation was cardiac arrest. Thromboembolic events were the first sign of NCCM in 3% (n = 10). Three patients had a CHD. Seven patients who presented with a thromboembolic event had a stroke, 2 had a kidney infarction, and 1 had a mesenteric occlusion. Thirty patients, of whom 16 had a mutation, were identified through family cardiologic family screening for HCM, DCM, sudden cardiac death, familial hypertension, or hemochromatosis. Cardiologic screening for other reasons identified 42 patients, of whom 12 had a mutation. Twenty-four (34%) of these 42 patients were asymptomatic, and 7 asymptomatic cases had a mutation.
Hypertension occurred frequently in adults (n = 62; 23%), particularly in adults without a mutation (p = 0.047) (Table 1). Left bundle branch block (LBBB) was significantly more common in adult patients with sporadic NCCM (27%) compared with the adult genetic (10%) and probably genetic cases (11%; p = 0.01) (Table 1). Information on echocardiographic, electrocardiographic, and cardiac magnetic resonance characteristics of NCCM patients is presented in Online Table 4.
Reduced ventricular systolic function
The risk of having LV systolic dysfunction was higher for genetic patients compared with the probably genetic and sporadic cases (p = 0.024), with the highest risk in patients with multiple mutations and TTN mutations (Tables 2 and 3⇓⇓ and the Central Illustration). LV systolic dysfunction occurred in 44% of the children and 58% of the adult patients (p = 0.067). LV dysfunction was observed more often than RV dysfunction (RV 14% and LV 53%). RV function was measured in 31 of the 52 pediatric patients (12 genetic, 5 probably genetic, and 14 sporadic) at admission; this assessment detected reduced RV function in 4 genetic cases (with DES de novo, PLN de novo, homozygous MYL2, and MYH7 defects) who also had LV systolic dysfunction, and also in 1 sporadic patient with normal LV function. The risk of having reduced RV function was increased in genetic patients (p = 0.008).
Major adverse cardiac events
During a median follow-up of 60 months (IQR: 18 to 113 months), MACE occurred in 14 (27%) children, and 58 (21%) adults experienced MACE during a median follow-up of 25 months (IQR: 4 to 58 months) (Table 2). An increased risk of MACE was observed in children with (probable) genetic NCCM (p = 0.025) (Figure 4A), children diagnosed at age younger than 1 year (hazard ratio [HR]: 2.10; 95% CI: 1.00 to 4.40; p = 0.048) (Table 4), and children with multiple mutations in MYBPC3 (HR: 5.20; 95% CI: 1.62 to 16.50; p = 0.006). Risk of MACE in children was also associated with LV systolic dysfunction (HR: 7.70; 95% CI: 1.70 to 34.70; p = 0.008). The risk for adverse events in sporadic children was low (HR: 0.10; 95% CI: 0.02 to 0.93; p = 0.043). No difference in risk of MACE was observed among the adults with genetic, probable genetic, and sporadic NCCM (Figure 4B).
LV systolic dysfunction was associated with an increased risk of MACE (HR: 1.7; 95% CI: 1.1 to 2.8; p = 0.028). In line with these observations, genetic patients with good LV function had a low risk of adverse cardiac events (p = 0.002) (Figure 4C). A low risk of MACE was observed in patients with an MYH7 mutation (HR: 0.17; 95% CI: 0.04 to 0.69; p = 0.013) (Table 4, Central Illustration). The reduced risk of MACE in patients with an MYH7 mutation remained after correction of LV systolic function. In sporadic patients, the risk of MACE was not related to LV function (Figure 4D); patients without a mutation and normal LV function had a similar risk of MACE as patients with LV systolic dysfunction.
Cardiac arrest occurred significantly more in female patients than in male patients (11% vs. 2%; p = 0.003). More women had an ischemic stroke than men (9% vs. 3%; p = 0.045). Patients with CHDs experienced stroke more often (with CHD: 56% vs. without CHD: 5%; p = 0.001).
In this large cohort of NCCM patients, we investigated the correlations between genetics, clinical presentation, and long-term outcomes. We showed that nearly one-third of the NCCM patients had a mutation in a cardiomyopathy gene. In this heterogeneous cardiomyopathy, age at diagnosis, LV systolic dysfunction, and risk of MACE were linked to genetic status. Children diagnosed with NCCM more often had a genetic cause than adults. LV systolic dysfunction at presentation and long-term outcome were related to genetics.
It is important to distinguish genetic NCCM because genetic status may add to prediction of risk for MACE and may guide clinical management and intensity of follow-up for specific groups of patients and their relatives. Children with a mutation were diagnosed frequently at younger than 1 year of age; they had cardiac symptoms, LV systolic dysfunction, and a high risk for MACE. In contrast, children with sporadic NCCM were diagnosed incidentally, had normal cardiac function, and low risk of MACE. In adults with a mutation, a high risk of MACE was strongly correlated with LV systolic dysfunction. However, risk of MACE in adults with sporadic NCCM was not determined by LV systolic dysfunction.
In approximately one-half (48%) of the NCCM patients genetics played a role; 32% of the patients had a mutation and 16% of the patients had familial disease without a mutation. Sporadic NCCM was more prevalent in adults than in children. These results suggested that, apart from genetic causes for NCCM, acquired (nongenetic) causes for hypertrabeculation might play a role, particularly in the sporadic adult cases (18). In addition, our results endorsed the heterogeneity of NCCM and the importance of genetics, simultaneously evoking questions on different etiologies for hypertrabicularization in children and adults.
Three of the 22 different cardiomyopathy genes were not reported previously in NCCM, expanding the genetic spectrum of NCCM with the DES, PLN, and RBM20 genes. In the genetic cases, mutations in MYH7, MYBPC3, and TTN genes were the most frequent. MYH7 was the most affected gene, as described previously (7,10). The risk of MACE was lower in MYH7 patients (5%). MYH7 was the only sarcomere gene associated with CHD; 4 patients with the MYH7 mutation had Ebstein anomaly (19). Compound heterozygosity of MYBPC3 was associated with severe early-onset NCCM. In 3 patients, TTN mutations co-occurred with MIB1 mutations, endorsing the hypothesis that a TTN mutation may not be a sufficient genetic cause for NCCM (20). TTN defects were not observed in pediatric cases. High prevalence of TTN mutations in women with a peripartum cardiomyopathy and in chemotherapy-induced cardiomyopathy (21–23) also suggested involvement of cofactors accumulated during life in the development of TTN-associated cardiomyopathies.
Acquired causes for NCCM are expected in a large proportion of patients, specifically, the sporadic adults. The role of acquired causes in late-onset NCCM challenges the general assumption of the embryological nature of hypertrabeculation. If NCCM is a developmental disorder, a higher rate of diagnosis would be expected shortly after birth or in childhood than the 16% of childhood cases we found in our cohort. Late-onset NCCM might be explained by an enhancement of a latent asymptomatic congenital defect by disruptions of cardiac homeostasis later in life. Recent studies endorsed the hypothesis that acquired causes might lead to characteristic hypertrabeculation. Conditions with an increased cardiac preload that are associated with hypertrabeculation include sickle cell anemia, pregnancy, and intensive sports (24–26). Our observation that LBBB was more prevalent in adults with sporadic NCCM might be explained by a role of increased cardiac preload in the development of hypertrabeculation. LBBB leads to higher end-diastolic volumes, which leads to an increased cardiac preload (27). Hypertension may also lead to increased preload and may be another secondary cause, because it was also more frequent in sporadic patients (28).
One-third of the mutations were found in patients who did not report relatives with a cardiomyopathy (i.e., when family history was negative). This illustrated that DNA testing should not be restricted to cases with a positive family history, and that DNA testing of patients without a family history is as important. DNA testing is important because when a mutation is found it allows families to have DNA testing and to accurately identify which relatives have a mutation and an increased risk. In this way, identifying the causative mutation facilitates genetic cascade screening. In addition, relatives who do not carry the mutation can be excluded from regular cardiac follow-up and can be reassured that there is no increased risk in their offspring.
The proportion of genetic patients is expected to be >48% because in 30% of the patients without a mutation, Sanger sequencing of a small number of cardiomyopathy genes was performed, and these might have a mutation in a cardiomyopathy gene that was not tested. Seventy-one (41%) of the sporadic cases had VUS that could be reclassified in the future as likely pathogenic. Moreover, cardiomyopathy genes, which have not been identified yet, might play a role in the familial cases without a mutation, as well as in the sporadic cases.
A referral bias of more severe cases could not be excluded. Consequently, asymptomatic or mildly affected cases might be underrepresented, leading to an overestimation of severe clinical features. In addition, we might have introduced a selection bias of symptomatic NCCM by including only index cases (to control for overrepresentation of genetic causes). By doing so, we might have missed asymptomatic cases that would only be recognized by family screening. We might have underestimated the role of genetic causes for NCCM because not all patients were tested for the complete genetic cardio-panel (∼45 genes). Some patients had a rare variant of unknown significance, which are currently not classified as disease-causing, but these might be reclassified as likely pathogenic in the future. In contrast, some variants, although they were classified by current stringent criteria as (likely) pathogenic, could turn out to be benign in the future.
We used the current, widely used diagnostic criteria for NCCM, despite the fact that they lack specificity, and that novel diagnostic criteria, preferably using both morphologic and genetic data, are needed. We could not currently rule out to have included patients with benign hypertrabeculation as NCCM. Family screening and obtaining accurate diagnosis of relatives was more difficult in families of adult patients; therefore, this might be one of the causes of the high prevalence of sporadic NCCM in adults. In addition, because of the retrospective design of our study, clinical data might have been missing. We might have underestimated heart failure–related events because we selected only patients with heart failure who required hospitalization.
NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM might complement prediction of outcome and subsequently guide management of patients with follow-up tailored to genetic status.
COMPETENCY IN MEDICAL KNOWLEDGE: NCCM is heterogeneous, and genetic factors play a more important role in children than in adults with this condition. Adverse cardiac events occur more often in mutation carriers with left ventricular systolic dysfunction than in sporadic cases.
TRANSLATIONAL OUTLOOK: Large follow-up studies are needed to confirm the genotype–phenotype correlations and guide genetically tailored management strategies for patients with NCCM and their families.
Dr. van Waning was supported by a grant from the Jaap Schouten Foundation.
All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial septal defect
- confidence interval
- congenital heart defect
- dilated cardiomyopathy
- hypertrophic cardiomyopathy
- hazard ratio
- interquartile range
- left bundle branch block
- left ventricular
- major adverse cardiac events
- magnetic resonance imaging
- noncompaction cardiomyopathy
- right bundle branch block
- right ventricular
- ventricular septal defect
- variant of unknown clinical significance
- Received November 22, 2017.
- Accepted December 8, 2017.
- 2018 American College of Cardiology Foundation
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