Juan Pablo Kaski

Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy.

Background— Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Methods and Results— Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1), the genes encoding desmin (DES), and the &ggr;-2 subunit of AMP kinase (PRKAG2) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2, ACTC, MYL3, and TNNI3 accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. Conclusions— This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised.

Long-Term Outcomes in Hypertrophic Cardiomyopathy Caused by Mutations in the Cardiac Troponin T Gene

Background— Hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene (TNNT2) has been associated with a high risk of sudden cardiac death (SCD) and mild left ventricular hypertrophy. However, previous studies are limited by sample size, cross-sectional design, and few data in relatives. Methods and Results— Five hundred fifty-two unrelated hypertrophic cardiomyopathy probands were screened for TNNT2 mutations. First-degree relatives were invited for clinical and genetic evaluation. Ninety-two individuals (20 probands and 72 relatives) carried TNNT2 mutations (51 [55%] male; 30±17 years). ECGs and echo were available in 87 (95%) and 88 (96%) individuals, respectively. ECG was normal in 13 (68%) children (<16 years) and 13 (19%) adults. Echo was normal in 18 (90%) children and 16 (24%) adults; 7 (10%) adults had a normal ECG and echo. Thirteen (65%) of 20 families had a history of SCD. Follow-up was available for 75 patients (mean, 9.9±5.2 years); 2 of 16 adults and 2 of 18 children with normal echoes developed left ventricular hypertrophy. Twenty-three (22%) received an implantable cardioverter-defibrillator (20 for primary prophylaxis). One child and 3 adults died of SCD and 2 adults were resuscitated from ventricular fibrillation. One patient had an appropriate implantable cardioverter-defibrillator discharge. The rate of cardiovascular death, transplant, and implantable cardioverter-defibrillator discharge was 1.6% (0.016 person/y; 95% confidence interval, 0.83–2.79%), and SCD 0.93% (0.0093 person/y; 95% confidence interval, 0.37–1.92%). Conclusions— Left ventricular hypertrophy is rare in children with TNNT2 mutations. Left ventricular hypertrophy is absent in the minority of adults, but most have an abnormal ECG. Despite adverse family histories, the rate of cardiovascular death during follow-up was similar to that reported in large referral populations.

The Congenital Heart Disease Genetic Network Study Rationale, Design, and Early Results

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.

Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle

Background—Familial dilated cardiomyopathy can be caused by mutations in the proteins of the muscle thin filament. In vitro, these mutations decrease Ca2+ sensitivity and cross-bridge turnover rate, but the mutations have not been investigated in human tissue. We studied the Ca2+-regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation. Methods and Results—Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC. Contraction was compared in skinned ventricular myocytes from the cTnC G159D patient and nonfailing donor heart. Maximal Ca2+-activated force was similar in cTnC G159D and donor myocytes, but the Ca2+ sensitivity of cTnC G159D myocytes was higher (EC50 G159D/donor=0.60). Thin filaments reconstituted with skeletal muscle actin and human cardiac tropomyosin and troponin were studied by in vitro motility assay. Thin filaments containing the mutation had a higher Ca2+ sensitivity (EC50 G159D/donor=0.55±0.13), whereas the maximally activated sliding speed was unaltered. In addition, the cTnC G159D mutation blunted the change in Ca2+ sensitivity when TnI was dephosphorylated. With wild-type troponin, Ca2+ sensitivity was increased (EC50 P/unP=4.7±1.9) but not with cTnC G159D troponin (EC50 P/unP=1.2±0.1). Conclusions—We propose that uncoupling of the relationship between phosphorylation and Ca2+ sensitivity could be the cause of the dilated cardiomyopathy phenotype. The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation.

Hypertrophic cardiomyopathy in children

Hypertrophic cardiomyopathy (HCM) is the second commonest form of heart muscle disease affecting children and adolescents and is a leading cause of sudden death in young athletes. The aetiology of HCM is heterogeneous in the paediatric population, and includes inborn errors of metabolism, neuromuscular disorders and malformation syndromes. However, most cases of apparently idiopathic HCM in childhood are caused by mutations in cardiac sarcomere protein genes. Patients with metabolic or syndromic HCM usually present in infancy or early childhood, whereas those with neuromuscular disorders are more frequently diagnosed in adolescence. The diagnosis of HCM in infants is often made during evaluation for a heart murmur or congestive heart failure. Older children are usually referred for evaluation of symptoms, electrocardiographic abnormalities or heart murmur, or for family screening following the diagnosis of HCM in a relative. Risk stratification in the paediatric population remains a challenge. As most cases of HCM are familial, evaluation of first-degree relatives and other family members at risk of inheriting the disease should be a routine component of clinical management.

The Classification Concept of the ESC Working Group on Myocardial and Pericardial Diseases for Dilated Cardiomyopathy

In the WHO/ISFC classification of 1996, cardiomyopathies were defined as primary myocardial disorders of unknown cause. Heart muscle disorders of known etiology or associated with systemic disorders were classified as secondary or specific heart muscle diseases. An expert panel of the American Heart Association has recently suggested a new scheme that combines genetic and clinical criteria. In this system, the term primary is used to describe cardiac diseases in which the heart is the sole or predominantly involved organ and secondary to describe diseases in which myocardial dysfunction is part of a systemic disorder. In a radical departure from convention, they also suggested that ion channelopathies and disorders of conduction should be considered cardiomyopathies as well. The ESC Working Group on Myocardial and Pericardial Diseases has taken a different approach based on the belief that a clinically oriented classification system in which heart muscle disorders are grouped according to ventricular morphology and function remains the clinically most useful method for diagnosing and managing patients and families with heart muscle disease. In the ESC position statement, cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality. In this article, this is illustrated by examples of dilated cardiomyopathy as familial/genetic forms and nonfamilial/ nongenetic forms.ZusammenfassungNach der WHO/ISFC-Klassifikation der Kardiomyopathien von 1996 wurden Kardiomyopathien nach ihrem hämodynamischen und morphologischen Phänotyp und ihrer Ätiologie eingeteilt. Primäre Kardiomyopathien waren Herzmuskelerkrankungen unbekannter Ursache, wohingegen derselbe Phänotyp als spezifische Kardiomyopathie oder Herzmuskelerkrankung bekannter Ursache als sekundäre Form klassifiziert wurde. Ein Expertenkomitee der American Heart Association hat hierzu im Jahr 2006 ein Schema vorgeschlagen, das genetische und klinische Kriterien vereint, die Begriffe primär und sekundär aber anders verwendet: Primäre Kardiomyopathien waren nach dieser Klassifikation Herzmuskelerkrankungen, die (nahezu) ausschließlich das Herz betrafen; sekundäre Herzmuskelerkrankungen umfassten Systemerkrankungen, bei denen die kardiale Dysfunktion nur eines unter verschiedenen Symptomen und/oder Organbeteiligungen darstellte. In einer radikalen Abkehr von bisherigen Konventionen wurden die Kanalopathien und Reizleitungsstörungen zu Kardiomyopathien umklassifiziert. Die ESC Working Group on Myocardial and Pericardial Diseases hat hierzu stets einen konträren Standpunkt vertreten, weil eine klinisch orientierte Klassifikation nach morphologischem Phänotyp und Funktion die klinische praktikabelste Einteilung für Diagnose und Management von Kardiomyopathiepatienten darstellen dürfte. Sie hat deshalb Kardiomyopathien unverändert als Herzmuskelerkrankungen definiert, bei denen der Herzmuskel strukturelle und funktionelle Abnormitäten aufweist, die sich nicht durch eine koronare Herzerkrankung, Hochdruck, eine Herzklappenerkrankung oder kongenitale Herzerkrankung erklären lassen. Dies wird an Beispielen der dilatativen Kardiomyopathie als familiäre/genetische Formen und als nichtgenetische/nichtfamiliäre Formen erläutert.

Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood

The role of familial disease in childhood dilated cardiomyopathy is unknown. A novel mutation in the cardiac Troponin C gene has been identified recently in a family with dilated cardiomyopathy. Here we present a subsequent case of dilated cardiomyopathy occurring in a child from the same family, and emphasise the implications for future screening and counselling.

Normalization of echocardiographically derived paediatric cardiac dimensions to body surface area: time for a standardized approach

The quantification of cardiac dimensions derived from echocardiography is important in paediatric cardiac practice. Evaluation of the size and growth of cardiac chambers, valves, and great vessels plays a key role in the management of congenital heart disease, from the initial decision-making in the neonatal period to the nature and timing of subsequent interventions. It may also be important in the assessment and risk stratification of children with ‘acquired’ heart disease such as hypertrophic cardiomyopathy or coronary artery involvement in Kawasaki disease. Body size and cardiac dimensions change dramatically during normal growth and development. Therefore, it is necessary to place in context the measured size of a given cardiac structure by correcting for body size, through the process of normalization. The paper by Neilan et al. 1 in this issue of the Journal is a timely addition to the literature on normalization in paediatric populations, and raises a number of important issues.

Prevalence of Sequence Variants in the RAS-Mitogen Activated Protein Kinase Signaling Pathway in Pre-Adolescent Children With Hypertrophic Cardiomyopathy

Background— Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. Methods and Results— Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ⩽13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. Conclusions— This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.

Prevalence of Sequence Variants in the RAS-MAPK Signaling Pathway in Pre-Adolescent Children with Hypertrophic Cardiomyopathy

Background— Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. Methods and Results— Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ⩽13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. Conclusions— This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.