Sarcomere Gene Mutations in Isolated Left Ventricular Noncompaction Cardiomyopathy Do Not Predict Clinical Phenotype

Probst, Susanne; Oechslin, Erwin; Schuler, Pia K.; Greutmann, Matthias; Boyé, Philipp; Knirsch, Walter; Berger, Felix; Thierfelder, Ludwig; Jenni, Rolf; Klaassen, Sabine

doi:10.1161/circgenetics.110.959270

Cited by 177 publications

(142 citation statements)

References 41 publications

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“…Whether contractile dysfunction is the mechanism that links mutant sarcomere protein to the morphologic features of LVNC is still uncertain. 13 In the majority of patients with familial cardiomyopathy owing to a variant in one of the genes encoding sarcomeric proteins, a single autosomal dominant pathogenic mutation is found. In contrast, our four patients were compound heterozygotes (two patients) or homozygous (two patients) for two truncating MYBPC3 variants, suggesting a cumulative effect.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

et al. 2014

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Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p. (Trp792fs) and c.2827C4T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C4T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n = 21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.

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Section: Discussionmentioning

confidence: 99%

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

et al. 2014

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“…21,22 There is, however, no clear genotype-phenotype association. 23 Genetic abnormalities may thus cause both structural congenital malformations and impaired left ventricular myocardial differentiation. Alternatively, hemodynamic alterations during fetal life may be a cofactor for the development of ventricular non-compaction in a patient with genetic predisposition.…”

Section: Since Its First Description Left Ventricular Non-compactionmentioning

confidence: 99%

Left ventricular non‐compaction: Prevalence in congenital heart disease

Stähli

Gebhard

Biaggi

et al. 2013

International Journal of Cardiology

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128

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INTRODUCTION: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare cardiomyopathy, originally described as an isolated disease without other structural cardiac abnormalities. The aim of this study was to explore the prevalence of LVNC among adults with different types of congenital heart disease. METHODS: From our databases we identified adults with congenital heart disease who fulfilled diagnostic criteria for LVNC. We report frequencies of associated congenital cardiac defects and the prevalence of LVNC among patients with different congenital heart defects. RESULTS: From a total of 202 patients with LVNC, 24 patients (12%; mean age 32±11years, 19 males) had additional congenital cardiac defects. Associated defects were left ventricular outflow tract abnormalities in 11 patients (46%), including 7 uni-or bicuspid aortic valves; two aortic coarctations; one diffuse aortic hypoplasia and one subaortic stenosis, Ebstein anomaly in 6 patients (25%), tetralogy of Fallot in two (8%), and double outlet right ventricle in one patient (4%). In our cohort, the prevalence of LVNC was highest among patients with Ebstein anomaly (6/40, 15%), followed by aortic coarctation (2/60, 3%), tetralogy of Fallot (3/129, 2%) and uni-or bicuspid aortic valves (7/963, 1%). CONCLUSION: In adults, various forms of congenital heart disease are associated with LVNC, particularly stenotic lesions of the left ventricular outflow tract, Ebstein anomaly, and tetralogy of Fallot. In the future, studying these patients in more depth may provide a better understanding of the interplay between genetic and hemodynamic factors that lead to the phenotype of LVNC.

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“…Mittels genetischer Diagnostik lässt sich mit 35-40 % im Vergleich zu AHF ein deutlich höherer Prozentsatz an Mutationen bei den betroffenen Personen mit LVNC identifizieren [23,25,29]. Dies könnte, trotz der großen Vielfalt an unterschiedlichen Genen, an einem gemeinsamen Entstehungsmechanismus liegen, der auf unterschiedliche Art und Weise während der Entwicklung gestört wird.…”

Section: Nicht-syndromale Strukturelle Herzfehlerunclassified