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Noncompaction cardiomyopathy is caused by a novel in‐frame desmin (DES) deletion mutation within the 1A coiled‐coil rod segment leading to a severe filament assembly defect

Published on Jun 1, 2019in Human Mutation4.453
· DOI :10.1002/humu.23747
Andrey V. Marakhonov1
Estimated H-index: 1
(Far Eastern Federal University),
Andreas Brodehl9
Estimated H-index: 9
(RUB: Ruhr University Bochum)
+ 16 AuthorsMikhail Skoblov2
Estimated H-index: 2
(Far Eastern Federal University)
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Abstract
  • References (30)
  • Citations (1)
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References30
Newest
#1Andreas Brodehl (RUB: Ruhr University Bochum)H-Index: 9
#2Anna Gaertner-Rommel (RUB: Ruhr University Bochum)H-Index: 6
Last. Hendrik Milting (RUB: Ruhr University Bochum)H-Index: 27
view all 3 authors...
Increasing usage of next-generation sequencing techniques pushed during the last decade cardiogenetic diagnostics leading to the identification of a huge number of genetic variants in about 170 genes associated with cardiomyopathies, channelopathies, or syndromes with cardiac involvement. Because of the biochemical and cellular complexity, it is challenging to understand the clinical meaning or even the relevant pathomechanisms of the majority of genetic sequence variants. However, detailed know...
6 CitationsSource
#1Ilona Schirmer (RUB: Ruhr University Bochum)H-Index: 3
#2Mareike Dieding (Bielefeld University)H-Index: 7
Last. Hendrik Milting (RUB: Ruhr University Bochum)H-Index: 27
view all 11 authors...
Background DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. Methods Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a histor...
4 CitationsSource
#1Jaap I. van Waning (EUR: Erasmus University Rotterdam)H-Index: 2
#2Kadir Caliskan (EUR: Erasmus University Rotterdam)H-Index: 21
Last. Danielle Majoor-Krakauer (EUR: Erasmus University Rotterdam)H-Index: 22
view all 24 authors...
Abstract Background The clinical outcomes of noncompaction cardiomyopathy (NCCM) range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death. Genetics play an important role in NCCM. Objectives This study investigated the correlations among genetics, clinical features, and outcomes in adults and children diagnosed with NCCM. Methods A retrospective multicenter study from 4 cardiogenetic centers in the Netherlands classified 327 unrelated NCCM patients into 3 categories: 1) ge...
39 CitationsSource
#1Francisco José Bermúdez-Jiménez (UGR: University of Granada)H-Index: 3
#2Víctor Carriel (UGR: University of Granada)H-Index: 17
Last. Juan Jiménez-Jáimez (UGR: University of Granada)H-Index: 9
view all 14 authors...
Background —Desmin ( DES ) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, DES mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia (iARVC/D), although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel DES -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia (...
12 CitationsSource
The normal function of the human myocardium requires the proper generation and utilization of energy and relies on a series of complex metabolic processes to achieve this normal function. When metabolic processes fail to work properly or effectively, heart muscle dysfunction can occur with or without accompanying functional abnormalities of other organ systems, particularly skeletal muscle. These metabolic derangements can result in structural, functional, and infiltrative deficiencies of the he...
28 CitationsSource
Background— Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype–phenotype correlations. Methods and Results— A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome...
15 CitationsSource
Aim. To perform clinical and instrumental examination and genetic testing using the method of exome sequencing of proband and his relatives of 1 and 2 degrees of kinship with myofibrillary myopathy and non-compaction cardiomyopathy. Material and methods . The object of the study: proband with non-compaction cardiomyopathy and his relatives of 1 and 2 degrees of kinship. All participants underwent clinical and instrumental examination including: blood collection for genetic testing, complete cell...
3 CitationsSource
#1Jeffrey A. Towbin (Cincinnati Children's Hospital Medical Center)H-Index: 120
#2Angela Lorts (Cincinnati Children's Hospital Medical Center)H-Index: 17
Last. John L. Jefferies (Cincinnati Children's Hospital Medical Center)H-Index: 19
view all 3 authors...
Summary Left ventricular non-compaction, the most recently classified form of cardiomyopathy, is characterised by abnormal trabeculations in the left ventricle, most frequently at the apex. It can be associated with left ventricular dilation or hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be induced by exercise or be persistent at re...
146 CitationsSource
#1Karim HniaH-Index: 15
Last. Jean-Francois LaporteH-Index: 97
view all 4 authors...
Desmin is a muscle-specific type III intermediate filament essential for proper muscular structure and function. In human, mutations affecting desmin expression or promoting its aggregation lead to skeletal (desmin-related myopathies), or cardiac (desmin-related cardiomyopathy) phenotypes, or both. Patient muscles display intracellular accumulations of misfolded proteins and desmin-positive insoluble granulofilamentous aggregates, leading to a large spectrum of molecular alterations. Increasing ...
25 CitationsSource
#1Sue Richards (OHSU: Oregon Health & Science University)H-Index: 5
#2Nazneen Aziz (Boston Children's Hospital)H-Index: 6
Last. Heidi L. Rehm (Harvard University)H-Index: 51
view all 12 authors...
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
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#1Miloš KubánekH-Index: 2
#1Milos KubanekH-Index: 9
Last. Tomas PalecekH-Index: 14
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Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathog...
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#1Andreas BrodehlH-Index: 9
#2Pour Hakimi SaH-Index: 1
Last. Hendrik MiltingH-Index: 27
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Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequen...
2 CitationsSource
In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original d...
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