The Genetic Landscape of Cardiomyopathies

Gerull, Brenda; Klaassen, S.; Brodehl, Andreas

doi:10.1007/978-3-030-27371-2_2

Cited by 41 publications

(49 citation statements)

References 212 publications

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“…In general, for about 50% of ACM patients a pathogenic mutation in the desmosomal genes can be identified [ 33 ]. Rare de novo mutations in isolated index patients [ 57 ] and rare copy number variants [ 58 , 59 ] might explain some cases without obvious familial/genetic history.…”

Section: Discussionmentioning

confidence: 99%

“…Progressive replacement of the myocardium against fibrotic and fatty tissue at the cellular and histological level is characteristic for ACM [ 31 , 32 ]. It is estimated that 5–10% of cases with ACM carry a pathogenic DSG2 mutation [ 33 ]. However, the majority of DSG2 variants are rare missense variants with unknown significance [ 3 , 34 ] ( , accessed on 20 January 2021).…”

Section: Introductionmentioning

confidence: 99%

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Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

Brodehl

Мешков

Myasnikov

et al. 2021

IJMS

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About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

Brodehl

Мешков

Myasnikov

et al. 2021

IJMS

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“…According to the HGMD, currently, nearly 200 different human cardiomyopathy-causing DSP mutations are known. In 5%–10% of all ACM patients, a pathogenic DSP mutation can be identified ( Gerull et al, 2019 ). Homozygous and heterozygous truncating mutations spread over the total DSP length are common.…”

Section: Animal Models For Acm Associated With Mutations In Desmosomamentioning

confidence: 99%

“…Heterozygous and homozygous pathogenic mutations in DSG2 and DSC2 , encoding the two cardiac desmosomal cadherins, have been identified in human ACM patients responsible for about 5% of cases ( Gerull et al, 2019 ; Brodehl et al, 2020 ). Using morpholino oligonucleotide injections, Heuser et al knocked down dsc2l in zebrafish larvae causing cardiac edema, decreased fractional shortening, and altered desmosomal structure ( Heuser et al, 2006 ).…”

Section: Animal Models For Acm Associated With Mutations In Desmosomamentioning

confidence: 99%

“…Z-bands are multiple-protein structures responsible for anchoring thin sarcomeric filaments as well as the giant sarcomere protein titin ( Luther, 2009 ) and impact the structural integrity of the sarcomeres. Mutations in several genes involved in Z-band formation are involved in genetic cardiomyopathies, including ACM ( Gerull et al, 2019 ).…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

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Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene

Takeda

Ueki

Abe

et al. 2023

Molec Gen & Gen Med

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Barth syndrome (BTHS) is an X‐linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3‐methylglutaconic aciduria. The causative pathogenic variants for BTHS are in TAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants in TAZ result in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant in TAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter the TAZ messenger RNA (mRNA) splicing process. TAZ mRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes of TAZ found an 8 bp deletion at the 3′ end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.

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The Genetic Landscape of Cardiomyopathies

Cited by 41 publications

References 212 publications

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene

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