Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

Rindler, Tara N.; Hinton, Robert B.; Salomonis, Nathan; Ware, Stephanie M.

doi:10.1038/srep39276

Cited by 19 publications

(13 citation statements)

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“…The proband was given a diagnosis of RCM at age 8, and upon echocardiogram was found to have an indexed left atrial volume of 72 ml/m 2 , right atrial enlargement, and left ventricular diastolic dysfunction (Figure b). Cardiac catheterization confirmed the diagnosis of RCM (Rindler, Hinton, Salomonis, & Ware, ). He underwent transplant at the age of 11 years.…”

Section: Resultsmentioning

confidence: 93%

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

et al. 2018

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Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.

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Section: Resultsmentioning

confidence: 93%

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

et al. 2018

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“…(43) This identified molecular pathway dysregulation that was common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation.…”

Section: Integrative Genomics: the Transcriptome In Pediatric Cardiommentioning

confidence: 99%

Genetics of paediatric cardiomyopathies

Ware

2017

Current Opinion in Pediatrics

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Purpose of review Pediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the pediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. Recent findings With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences from adult cardiomyopathy. Therapy targeted toward the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. Summary Genetics is moving at a rapid pace in pediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. While challenges in interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted toward the underlying genetic cause is beginning to be realized.

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“…Prior microarray studies suggested distinct gene expression signatures between HF etiologies [ 8 – 13 ]; but others failed to find distinctions [ 14 , 15 ]. Direct RNA-sequencing (RNA-seq) provides superior quantification of transcripts compared to microarrays and has been used to identify expression signatures between HF and non-failing (NF) hearts [ 16 ], novel transcriptional regulators and perturbed miRNA networks in ICM or DCM [ 17 , 18 ], pre- and post-LVAD transcriptomes [ 19 ], common HF genes in pediatric cardiomyopathy [ 20 ], and splicing, eQTL, and allelic expression in DCM [ 21 ]. Less progress has been made in refining differential expression between different adult HFrEF etiologies, particularly in human tissue models where access is often limited and sample sizes are small.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure

Sweet

Cocciolo²,

Slavov³

et al. 2018

BMC Genomics

167

158

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BackgroundCurrent heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.ResultsRNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.ConclusionsOur results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5213-9) contains supplementary material, which is available to authorized users.

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Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

Cited by 19 publications

References 50 publications

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

Genetics of paediatric cardiomyopathies

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure

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