Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Klaassen, Sabine; Probst, Susanne; Oechslin, Erwin; Gerull, Brenda; Krings, Gregor; Schuler, Pia K.; Greutmann, Matthias; Hürlimann, David; Yegitbasi, M.; Pons, Lucía; Gramlich, Michael; Drenckhahn, Jörg‐Detlef; Heuser, Arnd; Berger, Felix; Jenni, Rolf; Thierfelder, Ludwig

doi:10.1161/circulationaha.107.746164

Cited by 403 publications

(302 citation statements)

References 30 publications

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“…Like HCM, LVNC is genetically heterogeneous. 9,12 Recently, LVNC was shown to be mainly caused by heterozygous variants in genes encoding sarcomeric Biallelic pathogenic MYBPC3 mutations in neonates MW Wessels et al 15 e Not clear whether these variants are in cis or in trans. f A third variant in MYH7 was found.…”

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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“…None of those were identified in the ESP, but two SNPs (p.R1359C and p.R243H) were identified in ExAC database (Klaassen et al. 2008). These two variants predicted to be pathogenic with agreement of more than three prediction tools analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Family co‐segregation is a valuable tool for determining the pathogenicity of disease‐causing variants (Klaassen et al. 2008). Hoedemaekers et al.…”

Section: Discussionmentioning

confidence: 99%

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The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Abbasi

Jabbari

et al. 2015

Molec Gen & Gen Med

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BackgroundLeft ventricular non‐compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC‐associated variants that are common in the background population remains unknown. The aim of this study was to provide an updated list of previously reported LVNC‐associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false‐positive LVNC‐associated variants.Methods and ResultsThe Human Gene Mutation Database and PubMed were systematically searched to identify all previously reported LVNC‐associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine the functional effects of these variants. The prediction results of those identified in the ESP and ExAC and those not identified in the ESP and ExAC were compared. In 12 genes, 60 LVNC‐associated missense/nonsense variants were identified. MYH7 was the predominant gene, encompassing 24 of the 60 LVNC‐associated variants. The ESP only harbored nine and ExAC harbored 18 of the 60 LVNC‐associated variants. In total, eight out of nine ESP‐positive variants overlapped with the 18 variants identified in ExAC database.ConclusionsIn this article, we identified 9 ESP‐positive and 18 ExAC‐positive variants of 60 previously reported LVNC‐associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC.

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“…Other genes whose mutations have been implicated in both HCM and LVNC are TPM1 and MYBPC3 , encoding for tropomyosin 1 and cardiac myosin binding protein‐C, respectively 7, 8, 9, 10, 11, 12, 13…”

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confidence: 99%

Novel α‐Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical‐Pathologic Correlation

Frustaci

Luca

Guida

et al. 2018

JAHA

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BackgroundMutations of α‐actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.Methods and ResultsIn an Italian family of 7 subjects, 4 aged 10 (II‐1), 14 (II‐2), 43 (I‐4) and 46 years (I‐5), presenting abnormal ECG changes, dyspnea and palpitation (II‐2, I‐4, and I‐5), and recurrent cerebral ischemic attack (I‐5), underwent 2‐dimensional echo, cardiac magnetic resonance, Holter monitoring, and next‐generation sequencing gene analysis. Patients II‐2 and I‐5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age‐related prolongation of QRS duration. Two‐dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I‐4, I‐5, and II‐2 a progressive LV hypertrophy up to 22‐mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next‐generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC.ConclusionsNovel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

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Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Cited by 403 publications

References 30 publications

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

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

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Novel α‐Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical‐Pathologic Correlation

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