Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy

Minoche, André E.; Horvat, Claire; Johnson, Renée; Gayevskiy, Velimir; Morton, Sarah U.; Drew, Alexander P.; Woo, Kerhan; Statham, Aaron L.; Lundie, Ben; Bagnall, Richard D.; Ingles, Jodie; Semsarian, Christopher; Seidman, Jonathan G.; Seidman, Christine E.; Dinger, Marcel E.; Cowley, Mark J.; Fatkin, Diane

doi:10.1038/s41436-018-0084-7

Cited by 58 publications

(52 citation statements)

References 41 publications

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“…Variants were prioritised according to population frequency databases, variant impact, and in silico prediction tools, as described [10]. We assessed for CNVs and SVs using a clinically accredited detection pipeline (ClinSV, Minoche et al in preparation, and as described [12]). We used a software tool (VarSome [13]) for standard variant interpretation.…”

Section: Methodsmentioning

confidence: 99%

“…In order to compare WGS and WES, we assessed coverage of pathogenetic/likely pathogenic variants from ClinVar for genes from the dystonia panel using our inhouse WGS and WES datasets of the NA12878 cell line (see Minoche et al [12] for methods). We considered a cut-off of 15 reads for the reliable detection of variants [18].…”

Section: Coverage Of Disease-relevant Variants In Dystonia Genes: Wgsmentioning

confidence: 99%

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Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Kumar

Davis

Tchan

et al. 2019

Parkinsonism & Related Disorders

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Section: Methodsmentioning

confidence: 99%

Section: Coverage Of Disease-relevant Variants In Dystonia Genes: Wgsmentioning

confidence: 99%

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Kumar

Davis

Tchan

et al. 2019

Parkinsonism & Related Disorders

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“…It is a matter of ongoing debate whether whole genome sequencing (WGS) or whole exome sequencing (WES) in CMP would be necessary to provide more insight into the genetic disease mechanisms . The incremental yield of clinically actionable variants by WGS is limited by a paucity of genetic and functional evidence . In a study by Herkert et al, combining copy number variant analysis with stepwise trio‐based WES yielded a diagnosis in more than 50% of pediatric DCM patients .…”

Section: Discussionmentioning

confidence: 99%

“…42 The incremental yield of clinically actionable variants by WGS is limited by a paucity of genetic and functional evidence. 43 In a study by Herkert et al, combining copy number variant analysis with stepwise triobased WES yielded a diagnosis in more than 50% of pediatric DCM patients. 44 They identified patients with familial and non-familial DCM or a mixed cardiac phenotype with age at onset of CMP <18 years.…”

Section: Pediatric Cmp: Implications For Genetic Testing?mentioning

confidence: 99%

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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“…91 In comparison, WGS offers a more uniform coverage and greater breadth of coverage, as well as being better able to detect SNVs, indels, and SVs, including short and large CNVs. 89,92,93 As a result of the apparent advantages that WGS has over WES (better breadth of coverage and better variant identification), WGS has been referred to as "a better exome." 91,94 This is reflected in the diagnostic rate, where WES generally achieves in the range of 25 to 35%, as opposed to WGS, which is in the range of 40 to 60%.…”

Section: Comparison Of Sequencing Approachesmentioning

confidence: 99%

Next-Generation Sequencing and Emerging Technologies

Kumar

Cowley

Davis

2019

Semin Thromb Hemost

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198

160

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Genetic sequencing technologies are evolving at a rapid pace with major implications for research and clinical practice. In this review, the authors provide an updated overview of next-generation sequencing (NGS) and emerging methodologies. NGS has tremendously improved sequencing output while being more time and cost-efficient in comparison to Sanger sequencing. The authors describe short-read sequencing approaches, such as sequencing by synthesis, ion semiconductor sequencing, and nanoball sequencing. Third-generation long-read sequencing now promises to overcome many of the limitations of short-read sequencing, such as the ability to reliably resolve repeat sequences and large genomic rearrangements. By combining complementary methods with massively parallel DNA sequencing, a greater insight into the biological context of disease mechanisms is now possible. Emerging methodologies, such as advances in nanopore technology, in situ nucleic acid sequencing, and microscopy-based sequencing, will continue the rapid evolution of this area. These new technologies hold many potential applications for hematological disorders, with the promise of precision and personalized medical care in the future.

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Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy

Cited by 58 publications

References 41 publications

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

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

Next-Generation Sequencing and Emerging Technologies

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