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A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

ABSTRACT: BACKGROUND:As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing. METHODS AND RESULTS:Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C (MYBPC3) because of low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in prior panel testing: a pathogenic protein tyrosine phosphatase, non-receptor type 11 (PTPN11) variant and variants of uncertain significance in integrin-linked kinase (ILK) and filamin-C (FLNC). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions. CONCLUSIONS:WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care. CLINICAL TRIAL REGISTRATION:URL: https://clinicaltrials.gov. Unique identifier: NCT01736566.

SUBMITTER: Cirino AL

PROVIDER: S-EPMC5683423 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

Cirino Allison L AL Lakdawala Neal K NK McDonough Barbara B Conner Lauren L Adler Dale D Weinfeld Mark M O'Gara Patrick P Rehm Heidi L HL Machini Kalotina K Lebo Matthew M Blout Carrie C Green Robert C RC MacRae Calum A CA Seidman Christine E CE Ho Carolyn Y CY

Circulation. Cardiovascular genetics 20171001 5

<h4>Background</h4>As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing.<h4>Methods and results</h4>Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or fa ...[more]

PMID: 29030401

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Project description:Background and objectivesOwing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders.MethodsFrom January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance.ResultsA molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique.DiscussionES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

Dataset Information

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

Publications

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

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