The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Pugh, Trevor J.; Kelly, Melissa; Gowrisankar, Sivakumar; Hynes, Elizabeth; Seidman, Michael A.; Baxter, Samantha; Bowser, Mark J.; Harrison, B. D.; Aaron, Daniel; Mahanta, Lisa; Lakdawala, Neal K.; McDermott, Gregory; White, Emily; Rehm, Heidi L.; Lebo, Matthew S.; Funke, Birgit

doi:10.1038/gim.2013.204

Cited by 300 publications

(322 citation statements)

References 31 publications

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“…Additionally, although variants leading to loss of function of LMNA explain ~4% of DCM (Pugh et al. 2014), we identified only one individual with LMNA exon 1 deletion in 479 DCM patients (0.2%).…”

Section: Resultsmentioning

confidence: 92%

“…2010; Pugh et al. 2014). These efforts demonstrated that a broader testing strategy that targets a wide genetic spectrum is beneficial for achieving maximum clinical sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…2013; Pugh et al. 2014). Several genes are known to be susceptible to haploinsufficiency based on the high prevalence of heterozygous loss of function variants.…”

Section: Introductionmentioning

confidence: 99%

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Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Ceyhan‐Birsoy

Pugh

Bowser

et al. 2015

Molec Gen & Gen Med

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BackgroundDiagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied.MethodsWe performed single exon resolution NGS‐based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC.Results and ConclusionClinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders.

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Section: Resultsmentioning

confidence: 92%

“…2010; Pugh et al. 2014). These efforts demonstrated that a broader testing strategy that targets a wide genetic spectrum is beneficial for achieving maximum clinical sensitivity.…”

Section: Discussionmentioning

confidence: 99%

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Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Ceyhan‐Birsoy

Pugh

Bowser

et al. 2015

Molec Gen & Gen Med

Self Cite

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“…Alignment and variant calls were performed as previously described using BWA and GATK (version 1.0.4705). 18 For case 4, a microarray-based resequencing assay (GeneChip, Affymetrix, Santa Clara, CA, USA) was used, as previously described. 19 For case 3, droplet digital PCR probes (ddPCR; Bio-Rad, Hercules, CA, USA) were used to quantitate variant fraction using the manufacturer's protocol.…”

Section: Variant Analysismentioning

confidence: 99%

Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

et al. 2017

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Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal. Here we identified three variants, which have previously only been identified in isolated somatic JMML and other sporadic cancers, in four cases with a severe pre-or neo-natal lethal presentation of Noonan syndrome. These cases support the hypothesis that these stronger gain-of-function variants are rarely compatible with life.

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“…For this reason, large multi-disease gene panels are now frequently utilized for disorders with clinical and genetic heterogeneity including many inherited cardiac conditions. For example, gene panels for dilated cardiomyopathy (DCM) now typically also include genes associated with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) as these disorders can be the primary genetic etiology in a patient with DCM [2]. Similarly, sequencing tests for Noonan syndrome initially included only Noonan syndrome genes but today cover overlapping rasopathies [3].…”

mentioning

confidence: 99%

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Cited by 300 publications

References 31 publications

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes

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