Thomas Pickardt

Mutations in the sarcomere gene MYH7 in Ebstein anomaly

Background—Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding &bgr;-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. Methods and Results—Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. Conclusions—Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.

Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7

Ebstein’s anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein’s anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein’s anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein’s anomaly and LVNC and its implications for the clinical care for patients and their family members.

Legal and ethical consequences of international biobanking from a national perspective: the German BMB-EUCoop project

The international transfer of human biomaterial and data has become a prerequisite for collaborative biomedical research to be successful. However, although a national legal framework for ‘biobanking’ has already been formulated in many countries, little is known about how an international exchange of data and samples might affect the legal position of national biobanks and their donors. The German Telematics Platform and the Competence Network ‘Congenital Heart Defects’ jointly instigated a project (BMB-EUCoop) to (i) identify and assess the legal risks ensuing for biobanks and their donors in the context of Europe-wide research collaborations, (ii) devise practical recommendations to minimize or avoid these risks, and (iii) provide generic informational text, contracts and agreements to facilitate their practical implementation. Four different countries were included in the study; namely, the UK, Netherlands, Austria and Switzerland. The results of the study indicate that the degree of similarity between legal systems in different countries varies according to the respective field of jurisdiction. Although personality and property rights have long been enshrined in virtually identical pieces of law, the applicable medical professional regulations were found to be somewhat heterogeneous. Furthermore, clear-cut differences were often found to be lacking between regulations that reflect either ‘soft law’ or the nationally binding ‘hard law’ that has emerged from it. In view of the potential ambiguities, the experts uniformly concluded that the rights and interests of national (in this case, German) biobanks and their donors would be best protected by explicitly addressing any uncertainties in formal contractual agreements.

A Biobank for Long-term and Sustainable Research in the Field of Congenital Heart Disease in Germany

Congenital heart disease (CHD) is the most frequent birth defect (0.8%–1% of all live births). Due to the advance in prenatal and postnatal early diagnosis and treatment, more than 90% of these patients survive into adulthood today. However, several mid- and long-term morbidities are dominating the follow-up of these patients. Due to the rarity and heterogeneity of the phenotypes of CHD, multicenter registry-based studies are required. The CHD-Biobank was established in 2009 with the aim to collect DNA from patients and their parents (trios) or from affected families, as well as cardiovascular tissues from patients undergoing corrective heart surgery for cardiovascular malformations. Clinical/phenotype data are matched to the International Paediatric and Congenital Cardiac Code (IPCCC) and the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). The DNA collection currently comprises samples from approximately 4200 participants with a wide range of CHD phenotypes. The collection covers about 430 trios and 120 families with more than one affected member. The cardiac tissue collection comprises 1143 tissue samples from 556 patients after open heart surgery. The CHD-Biobank provides a comprehensive basis for research in the field of CHD with high standards of data privacy, IT management, and sample logistics.

Mutations in the Sarcomere Protein Gene MYH7 in Ebstein's Anomaly

Background—Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding &bgr;-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. Methods and Results—Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. Conclusions—Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.

Toward evidence-based diagnosis of myocarditis in children and adolescents: Rationale, design, and first baseline data of MYKKE, a multicenter registry and study platform

Aims The aim of this registry is to provide data on age‐related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis. Study design and results After an initial 6‐month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age<18 years and hospitalization for suspected myocarditis as leading diagnosis at the discretion of the treating physician. By December 31, 2015, fifteen centers across Germany were actively participating and had enrolled 149 patients. Baseline data reveal 2 age peaks (<2 years, >12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation. Summary MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real‐world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches.

Mutations in the Sarcomere Gene MYH7 in Ebstein AnomalyClinical Perspective

Background—Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding &bgr;-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. Methods and Results—Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. Conclusions—Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.