Biallelic mutation in
            <i>MYH7</i>
            and
            <i>MYBPC3</i>
            leads to severe cardiomyopathy with left ventricular noncompaction phenotype

Kolokotronis, Konstantinos; Kühnisch, Jirko; Klopocki, Eva; Dartsch, Josephine; Rost, S.; Huculak, Cathleen; Mearini, Giulia; Störk, Stefan; Carrier, Lucie; Klaassen, Sabine; Gerull, Brenda

doi:10.1002/humu.23757

Cited by 24 publications

(24 citation statements)

References 48 publications

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“…The vast majority of detected VOI were heterozygous, nevertheless; we observed two homozygous ( NEXN , TNNI3 ), and two compound heterozygous ( DSC2 , MYBPC3 ) VOI. In one case, we identified compound heterozygous mutation of MYBPC3 p.S858R with complete deletion of the MYBPC3 gene on the second allele …”

Section: Resultsmentioning

confidence: 81%

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Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

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Section: Resultsmentioning

confidence: 81%

“…In one case, we identified compound heterozygous mutation of MYBPC3 p.S858R with complete deletion of the MYBPC3 gene on the second allele. 19 T A B L E 2 Genetic variants of 80 index patients with pediatric cardiomyopathy…”

Section: Homozygous/compound Heterozygous Voimentioning

confidence: 99%

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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“…In another patient with HCM (#23), a pathogenic missense variant in MYH7 was detected in compound heterozygous state with a truncating splice variant in the same gene. A subsequent segregation analysis showed that the truncating variant was not associated with a clinical phenotype in the heterozygous state but led to a severe cardiomyopathy phenotype with non-compaction features in the compound heterozygous state [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

Kolokotronis

Pluta

Klopocki

et al. 2020

JCM

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Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.

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“…Since the discovery of MYH7, the first causative gene for HCM, more than 100 genes have been linked to cardiomyopathies (Geisterfer-Lowrance et al, 1990;Tanigawa et al, 1990;Marian and Braunwald, 2017;Muchtar et al, 2017;Yotti et al, 2019;James et al, 2020). Beyond a monogenic disease, findings from next-generation sequencing (NGS) suggest multiple genetic hits could contribute to phenotypic severity of cardiomyopathies (Xu et al, 2010;Harakalova et al, 2015;Kolokotronis et al, 2019). Both phenotypic and genetic heterogeneity strongly suggest that precision medicine should be practiced to treat cardiomyopathies of various causes (Fatkin et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

Ding

2020

Front. Physiol.

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Cardiomyopathies are a highly heterogeneous group of heart muscle disorders. More than 100 causative genes have been linked to various cardiomyopathies, which explain about half of familial cardiomyopathy cases. More than a dozen candidate therapeutic signaling pathways have been identified; however, precision medicine is not being used to treat the various types of cardiomyopathy because knowledge is lacking for how to tailor treatment plans for different genetic causes. Adult zebrafish (Danio rerio) have a higher throughout than rodents and are an emerging vertebrate model for studying cardiomyopathy. Herein, we review progress in the past decade that has proven the feasibility of this simple vertebrate for modeling inherited cardiomyopathies of distinct etiology, identifying effective therapeutic strategies for a particular type of cardiomyopathy, and discovering new cardiomyopathy genes or new therapeutic strategies via a forward genetic approach. On the basis of this progress, we discuss future research that would benefit from integrating this emerging model, including discovery of remaining causative genes and development of genotype-based therapies. Studies using this efficient vertebrate model are anticipated to significantly accelerate the implementation of precision medicine for inherited cardiomyopathies.

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Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype

Cited by 24 publications

References 48 publications

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

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