Cardiomyopathy In Children Research Articles

Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives’ recurrence risk calculation. The previous points represent a cornerstone in patients’ empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective “autophagy” process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.

Arrhythmogenic cardiomyopathy in children according to “Padua criteria”: Single pediatric center experience

IntroductionThe aim of this study was to report clinical and arrhythmic features in a pediatric population affected by arrhythmogenic cardiomyopathy (ACM). Moreover, we assessed the concordance between the 2010 International Task Force criteria (ITF) and the 2020 Padua criteria. MethodsInclusion criteria were “definite” or “borderline” ACM diagnosed according to the “Padua criteria” in patients <18 years old. History, electrocardiograms, ECG-holter monitorings, exercise testings, imaging investigations, electrophysiological studies, genetic testings and follow-up data were collected. ResultsWe enrolled 21 patients (mean age 13.9 ± 2 years). Most of them presented for minor arrhythmias. Premature ventricular complexes burden was 7.9 ± 10%. Cardiac magnetic resonance (19/21, 90.5% patients) showed right ventricular (RV) dilatation, wall motion abnormalities and late gadolinium enhancement (LGE) of both ventricles as predominant features [in 9 patients (52.9%) LGE left ventricle]. Genetic results (19/21 patient) showed compound heterozygous variants in 3/19 patients (15.8%), digenic in 3/19 (15.8%) and single in 6/19 (31.6%). Cardiac defibrillator (ICD) was indicated in 15 patients (71.4%): 6 in class I, 7 in class IIa, 2 in class IIb. Appropriate shocks occurred in 2 patients (13.3%), follow-up 5.46 ± 3.17 years According to 2010 ITF criteria: among the 18 patients with a “definite” ACM diagnosis, one patient would have had a “borderline” diagnosis, three a “possible” diagnosis and one no diagnosis and among the three patients with “borderline” diagnosis two would have had a “possible” diagnosis. ConclusionsPediatric ACM can be diagnosed in the majority of cases secondary to incidental finding of simple ventricular arrhythmias. PVC burden is low and exercise induced arrhythmias rarely occur. Few patients with ICD experience appropriate shocks. “Padua criteria” improve the diagnostic accuracy.

Genetic Basis of Childhood Cardiomyopathy

Cardiomyopathy in children is less well described than in adults. We evaluated clinical diagnoses and genetic causes of childhood cardiomyopathy, and outcomes of cascade genetic testing in family members.

Genetic Basis of Childhood Cardiomyopathy

Genetic Basis of Childhood Cardiomyopathy

245 Arrhythmogenic cardiomyopathy in children according to ‘padua criteria’: single paediatric centre experience

Abstract Aims Arrhythmogenic cardiomyopathy (ACM) is a rare disease in children. The purpose of this study is to describe the main features of our paediatric patients with ACM providing a contribution for diagnostic work-up and therapeutic decisions. Methods and results Eligibility criteria of the study was ACM diagnosed at age &amp;lt;18 years old. We enrolled 21 patients (mean age at diagnosis 13.9 ± 2 years). Holter monitoring showed premature ventricular complexes (PVCs) burden of 7.9 ± 10% (range: 1–35%). Exercise testing showed suppression of PVCs during exercise in most patients (44.4%). Cardiac magnetic resonance was performed in 17/21 (81%) patients. Right ventricular (RV) dilatation, segmental wall motion abnormalities, and late gadolinium enhancement of both ventricles were the predominant features. Genetic results were available in 19/21 patients. 3/19 (15.8%) had compound heterozygous variants, 3/19 (15.8%) digenic variants, and 6/19 (31.6%) a single variant. EPS was performed in 15/21 (75%). Ventricular tachycardia was inducible in 3/15 (20%) and ventricular fibrillation occurred in 1/15 (6.7%). Implantable cardiac defibrillators (ICDs) were implanted in 15 patients (71.4%). ICD therapies were released in two patients during follow-up (2009–2021). No patients died suddenly. Conclusions Paediatric ACM can be diagnosed in the majority of cases secondary to: incidental finding of minor arrhythmias or due to positive family history. PVCs burden is not elevated and exercise-induced arrhythmias occur in a minority of patients. ICD may be indicated in most patients even if follow-up during the paediatric age can be reassuring. Multicentric observation is highly needed to derive conclusions in children.

Changes of serum uric acid and its clinical correlation in children with dilated cardiomyopathy.

BackgroundDilated cardiomyopathy (DCM) is the most common type of childhood cardiomyopathy and uric acid (UA) is considered closely associated with cardiovascular disease. There are few reports about the relationship between serum UA level and DCM in children, and the present study aimed to analyze the changes and clinical correlation of the two.MethodsThe clinical data of 49 children under 16 years old and who were hospitalized with DCM, and 44 healthy children who underwent physical examination in the same period at Tianjin Children’s Hospital from June 2015 to November 2019 were analyzed retrospectively.ResultsThe 49 children in the case group included 17 males and 32 females, aged from 2 to 172 months. The case group were divided into New York Heart Association (NYHA) functional class I (n=2), class II (n=17), class III (n=11), and class IV (n=19). The 44 healthy children selected as the control group included 20 males and 24 females aged from 2 to 161 months. The serum UA level was detected, and an ultrasonic cardiogram was conducted in each child. The serum UA level, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left atrial diameter (LAD) of the case group were higher than that of the control group, while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower than that of the control group, and significant statistical differences were seen between the two groups (P<0.01). The serum UA level, LVEDD, LVESD, and LAD of NYHAIII–IV class patients were higher than that of the NYHAI–II class, but LVEF and LVFS were lower than that of the NYHA I–II class, and there were significant statistical differences between the two groups (P<0.01). Statistical correlations were seen between the serum UA level and NYHA functional class, LVEDD, LVESD, LAD, LVEF, and LVFS (rs=0.599, 0.567, 0.579, 0.475, −0.333, −0.341, respectively, P<0.05).ConclusionsElevated serum UA levels exist in children with DCM and correlate with NYHA functional class and ultrasonic values. Change in serum UA levels may be used as a biomarker reflecting the severity of DCM in children.

Long-Term Outcomes and Prognosticators of Pediatric Primary Dilated Cardiomyopathy in an Asian Cohort.

Background: Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy. The epidemiological profiles and prognosticators of clinical outcomes in Asian populations are not well elucidated.Methods: Data of 104 children aged <18 years with a diagnosis of primary DCM from January 1990 to December 2019 in our institutional database were retrospectively investigated. Relevant demographic, echocardiographic, and clinical variables were recorded for analysis. A P <0.05 was considered statistically significant.Results: The median age at diagnosis was 1.4 years (interquartile range = 0.3–9.1 years), and 52.9% were males. During a median follow-up duration of 4.8 years, 48 patients (46.2%) were placed on the transplantation waitlist, and 52.1% of them eventually received heart transplants. An exceptionally high overall waitlist mortality rate was noted (27.1%), which was even higher (43.5%) if the diagnostic age was <3 years. The 1-, 5-, and 10-year transplant-free were 61.1, 48.0, and 42.8%. Age at diagnosis >3 years and severe mitral regurgitation at initial diagnosis were independent risk factors for death or transplantation (hazard ratios = 2.93 and 3.31, respectively; for both, P <0.001). In total, 11 patients (10.6%) experienced ventricular function recovery after a median follow-up of 2.5 (interquartile range = 1.65–5) years. Younger age at diagnosis was associated a higher probability of ventricular function recovery.Conclusions: Despite donor shortage for heart transplantation and subsequently high waitlist mortality, our data from an Asian cohort indicated that transplant-free long-term survival was comparable with that noted in reports from Western populations. Although younger patients had exceptionally higher waitlist mortality, lower diagnostic age was associated with better long-term survival and higher likelihood of ventricular function recovery.

Idiopathic Restrictive Cardiomyopathy in Children

Idiopathic Restrictive Cardiomyopathy in Children

Spectrum of Clinical Features and Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children

Background: Left ventricular noncompaction (LVNC) is a genetically determined cardiomyopathy that occurs following a disruption of endomyocardial morphogenesis. The purpose of this study was to identify the clinical characteristics and genetic profile of children with LVNC. Methods: From February 2008 to July 2020, a total of 32 children (median 11.5 years) with LVNC were prospectively enrolled and followed up for a median of 4.02 years. Diagnosis was made based on characteristic features of LVNC in echocardiography and cardiovascular magnetic resonance (CMR). Patients’ clinical symptoms, family history, ECG, Holter ECG, and genetic tests were also evaluated. Results: The most common presenting symptom was heart failure (31% of children). ECG abnormalities were noted in 56% of patients. The most prominent features were ventricular arrhythmias, sinus bradycardia, and paroxysmal third-degree atrioventricular block. Most of the patients (94%) met the criteria for LVNC and CMR confirmed this diagnosis in 82% of cases. The molecular etiology was found in 53% of children. Conclusion: Although heart failure and arrhythmias were very frequent in our study group, thromboembolic events and genetic syndromes were rare. For the accurate and reliable assessment of children with LVNC, it is necessary to get to know their family history and detailed clinical profile.

Clinical features and natural history of RASopathy-associated hypertrophic cardiomyopathy in children

Abstract Background The RASopathies are a group of genetic disorders caused by germline mutations in genes encoding components of the RAS/MAPK signalling pathway and frequently associated with hypertrophic cardiomyopathy (HCM). The clinical features and outcomes of RASopathy-related HCM are incompletely understood and most published studies are limited by relatively small numbers and incomplete clinical characterisation. Purpose To describe the clinical features outcomes in a large, single-centre cohort of patients with RASopathy-associated HCM diagnosed &amp;lt;18 years. Methods Data from 105 patients [68 (64.8%) males] diagnosed in childhood with RASopathy-associated HCM at a single specialist centre between 1985 and 2020 were retrospectively analysed. Results The RASopathy diagnosis was Noonan syndrome in 69 patients (65.7%); NSML in 10 (9.5%); CFC in 6 (5.7%); Costello in 5 (4.8%) and 15 patients (14.2%) had another Noonan-like variant. 72 patients (68.6%) had a pathogenic/likely pathogenic variant in a RAS-MAPK gene, most commonly PTPN11 [n=25 (34.7%)], followed by RAF 1 [n=13 (18.1%)]. 100 patients (95.2%) were probands, 9 (8.6%) had family history of cardiomyopathy and 2 (1.9%) family history of sudden cardiac death (SCD). 52 (49.5%) had concomitant congenital heart defects (CHD) [ASD 13 (25%), VSD 6 (11.5%), PDA 1 (1.9%), &amp;gt;1 CHD 32 (61.5%)]. 29 (27.6%) had symptoms at baseline assessment and 56 (53.3%) were on cardiac medication. The distribution of left ventricular hypertrophy (LVH) was concentric in 47 (44.7%); 32 (30.5%) had asymmetric septal hypertrophy (ASH), and undocumented in 25 patients (23.8%). 45 patients (42.9%) had biventricular hypertrophy (BVH). Resting left ventricular outflow tract obstruction (LVOTO) was present in 39 (37.1%) with haemodynamically significant LVOTO (≥50mmHg) in 23 (21.9%). Resting right ventricular outflow tract obstruction (RVOTO) was present in 21 (20%). Over a median follow up time of 6 years, 19 patients (18.1%) died [1 (5.3%) SCD; 2 (10.5%) due to Heart Failure-related death; 1 (5.3%) due to another CVS cause; 5 (26.3%) due to a non-CVS cause and for 10 (52.6%) cause of death was unknown]. Incidence rate of death was calculated at 2.7 deaths per 100 person-years. Surgical septal myectomy was performed in 9 patients (8.6%) and 3 (2.9%) underwent cardiac transplantation. 14 patients (13.3%) suffered arrhythmic events [atrial tachycardia 6 (42.9%), Non-Sustained Ventricular Tachycardia 4 (3.8%), and Ventricular Tachycardia/Ventricular Fibrillation 4 (3.8%)]. Conclusion To our knowledge, this is the largest cohort of RASopathy-associated HCM. The findings show a heterogeneous clinical presentation with a high prevalence of morbidity and mortality. Further work is needed to determine predictors of outcome in this population. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Onassis Foundation

WHOLE GENOME SEQUENCING IDENTIFIES NOVEL CRYPTIC SPLICE SITE VARIANTS IN CHILDREN WITH CARDIOMYOPATHY

<h3>BACKGROUND</h3> Cardiomyopathy is a genetic disorder of heart muscle; 2/3 of cases are gene-elusive on panel testing. Cryptic splice site variants disrupt the normal pattern of mRNA splicing through the creation of novel exon boundaries, resulting in abnormal protein isoforms. These variants are not routinely evaluated during genetic testing in cardiomyopathy. Our objective was to identify the contribution of cryptic splice site variants in childhood cardiomyopathy. <h3>METHODS AND RESULTS</h3> Cryptic splice site variants were identified using the SpliceAI software in whole genome sequencing data from 231 unrelated pediatric cardiomyopathy probands enrolled in the Heart Centre Biobank. Rare variants (gnomAD population allele frequency < 0.01%) in cardiomyopathy genes were prioritized. RNAseq and proteomics data from available matched myocardial samples were assessed for altered gene splicing and/or expression. Eleven putatively pathogenic cryptic splice-altering variants were detected in 5% of cases in CTNNA3, DSP, FHOD3, FKTN, FLNC, LDB3, MYBPC3, and VCL. FLNC:c.3791-1G>C, FLNC:c.3790+5G>A, and CTNNA3:c.-6+12024G>A were validated in cases with available tissue data (Figure 1). All three variants were associated with altered mRNA splicing and reduced protein abundance. <h3>CONCLUSION</h3> Cryptic splice site variants may contribute to the genetics of cardiomyopathy through altered mRNA splicing and reduced expression of disease genes. These findings highlight the importance of searching not only for canonical splice site but also cryptic splice site variants as part of the genetic evaluation of cardiomyopathy.

Hypertrophic cardiomyopathy in children.

Hypertrophic cardiomyopathy (HCM) characterized by asymmetric ventricular septal hypertrophy, is the commonest cause of sudden cardiac death (SCD) in the young. The underlying etiology of HCM in the childhood and adolescent patients is diverse. Moreover, the prognosis of pediatric HCM depends on the age of presentation and etiology. Despite the complexity of children with obstructive HCM, surgical treatment results in a favorable outcome for carefully selected patients in experienced tertiary referral center in contemporary era. Implantable cardioverter-defibrillator (ICD) remains the most effective and reliable treatment to prevent SCD. New pediatric SCD risk prediction model, which has good discrimination and calibration and can distinguish patients who are most benefit from an ICD implantation, is expected to be further refined in the future.

Pediatric genetic cardiomyopathies: Genetic profile and genotype–phenotype correlations

Genetic cardiomyopathies (CM) affect 1–1.5 children per 100,000 each year. Five subtypes of cardiomyopathy exist, dilated CM (DCM) and hypertrophic CM (HCM) being the most common. This study aimed to establish the genetic profile of CM in children in the French South-East Region and describe the genotype–phenotype correlations. Retrospective analysis of children with CM diagnosed < 18 years in the French South-East Region, after exclusion of mitochondrial and other secondary causes. Retrospective study of genotype–phenotype correlations and genetic analyses performed. Completion of the gene panel according to current scientific data was performed for incomplete panels. Exome sequencing was proposed for patients without identified mutation. Eighty-three children were included from 2005 to 2019. Thirty-one (31%) patients had HCM, 22 (27%) had CMD, 10 (12%) had left ventricular non-compaction, 5 (6%) had restrictive CM and 13 (16%) had “mixed” CM. The mean age at diagnosis was 4.9 years (0–16.6). CM was discovered because of presence of a murmur in 29% of cases, signs of heart failure in 19% and cardiogenic shock in 8.5%. Thirty percent of the children required a heart transplant. 9(11%) patients died during the course of the study at a mean age of 8.4 years (±7). Genetic investigations had been performed in 66 (80%) patients, with a mutation found in 61% of them. MYH7 (35% of cases, often associated with HCM), MYBPC3 (10%) and TTNT2 (7.5%) were the genes most frequently found as involved with the CM. Further analysis (64 genes) is underway in 13 patients, with negative or incomplete panel or in those not yet tested. Genotype–phenotype correlations are in progress. Exome sequencing analysis is in progress for 3 patients with a negative complete panel, and their parents. Our preliminary data show a pathogenic mutation in 60% of the tested CM, in our pediatric population. Additional genetic analyses and genotype–phenotype correlations are currently in progress.

Hidden familial cardiomyopathies in children: Role of genetic testing

Pediatric cardiomyopathies harbour significant phenotypic and genetic heterogeneity. Genetic testing is essential for the initial evaluation and the ongoing care of child and family, although challenges remain regarding its appropriate clinical implementation in minors. We here discuss the key role of genetic diagnosis in the clinical management of two patients.

Early Outcomes of Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy in Children With Noonan Syndrome

Noonan syndrome (NS) is a genetic syndrome causing obstructive hypertrophic cardiomyopathy (HCM) in infants. Studies of cardiac surgery in pediatric HCM patients with NS (NS-HCM) are lacking. We aim to characterize the early disease course of young NS-HCM patients before adolescence and assess their complications and survival condition after septal myectomy. Pediatric obstructive HCM patients who underwent septal myectomy at age 10 years or under were enrolled consecutively between 2009 and 2019. Ten patients with NS and 43 non-NS patients were enrolled in our study. NS-HCM patients were diagnosed at a younger age (5.00 ± 7.48 months vs. 18.73 ± 26.96 months) and more often had biventricular outflow tract obstruction (90.00% vs 30.23%). The surgical treatment can significantly reduce the pressure gradient of the outflow tract. More NS-HCM patients had biventricular reconstruction (70.00% vs 25.58%). The overall survival rates in all patients were 98.04% during 5-year follow-up, respectively. Complete heart block (CHB) was the most prevalent complication in patients with NS and tended to be more common than in non-NS patients (20% vs 7.32%). No sudden cardiac death (SCD) occurred in CHB patients who had pacemaker implantation. Biventricular reconstruction was the risk factor for CHB. Septal myectomy is safe and effective surgery to relieve obstruction in young age pediatric obstructive NS-HCM patients. Postoperative CHB is a common complication, especially in patients who underwent biventricular reconstruction. The implantation of pacemaker can protect CHB patients from SCD and improve their prognosis.

Overview of Cardiomyopathies in Childhood.

Paediatric cardiomyopathies are a heterogenous group of rare disorders, characterised by mechanical and electrical abnormalities of the heart muscle. The overall annual incidence of childhood cardiomyopathies is estimated at about 1 per 100,000 children and is significantly higher during the first 2 years of life. Dilated cardiomyopathies account for approximately half of the cases. Hypertrophic cardiomyopathies form the second largest group, followed by the less common left ventricular non-compaction and restrictive phenotypes. Infectious, metabolic, genetic, and syndromic conditions account for the majority of cases. Congestive heart failure is the typical manifestation in children with dilated cardiomyopathy, whereas presenting symptoms are more variable in other phenotypes. The natural history is largely influenced by the type of cardiomyopathy and its underlying aetiology. Results from a national population-based study revealed 10-year transplant-free survival rates of 80, 62, and 48% for hypertrophic, dilated and left ventricular non-compaction cardiomyopathies, respectively. Long-term survival rates of children with a restrictive phenotype have largely been obscured by early listing for heart transplantation. In general, the majority of adverse events, including death and heart transplantation, occur during the first 2 years after the initial presentation. This review provides an overview of childhood cardiomyopathies with a focus on epidemiology, natural history, and outcomes.

Novel pathogenic variant of MYBPC3 responsible for hypertrophic cardiomyopathy.

This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872-967) domain and deletion of Ig-like C2-type 6 (p971-1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181-1274) domains, in which p1253-1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children.

Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

Correction to: Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

Correction to: Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

BackgroundPediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices.Methods and ResultsChildren with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes.ConclusionsA definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.