Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies.

Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Meder, B., Haas, J., Keller, A., Heid, C., Just, S., Borries, A., Boisguerin, V., Scharfenberger-Schmeer, M., Stähler, P., Beier, M., Weichenhan, D., Strom, T. M, Pfeufer, A., Korn, B., Katus, H. A, & Rottbauer, W. Circulation. Cardiovascular genetics, 4:110–122, April, 2011.
doi abstract bibtex

Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner. We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM. The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner.

@Article{Meder2011a,
  author          = {Meder, Benjamin and Haas, Jan and Keller, Andreas and Heid, Christiane and Just, Steffen and Borries, Anne and Boisguerin, Valesca and Scharfenberger-Schmeer, Maren and Stähler, Peer and Beier, Markus and Weichenhan, Dieter and Strom, Tim M and Pfeufer, Arne and Korn, Bernhard and Katus, Hugo A and Rottbauer, Wolfgang},
  title           = {Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies.},
  journal         = {Circulation. Cardiovascular genetics},
  year            = {2011},
  volume          = {4},
  pages           = {110--122},
  month           = apr,
  issn            = {1942-3268},
  abstract        = {Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner. We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM. The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner.},
  chemicals       = {Carrier Proteins, Codon, Nonsense, MYH7 protein, human, myosin-binding protein C, integrin-linked kinase, Protein-Serine-Threonine Kinases, Cardiac Myosins, Myosin Heavy Chains},
  citation-subset = {IM},
  completed       = {2011-08-10},
  country         = {United States},
  doi             = {10.1161/CIRCGENETICS.110.958322},
  issn-linking    = {1942-3268},
  issue           = {2},
  keywords        = {Adult; Base Sequence; Cardiac Myosins, genetics; Cardiomyopathy, Dilated, diagnosis, genetics; Cardiomyopathy, Hypertrophic, diagnosis, genetics; Carrier Proteins, genetics; Child; Codon, Nonsense; Female; Frameshift Mutation; Gene Deletion; Genetic Heterogeneity; Humans; Male; Middle Aged; Mutation, Missense; Myosin Heavy Chains, genetics; Point Mutation; Protein-Serine-Threonine Kinases, genetics; Sequence Analysis, DNA, methods},
  nlm-id          = {101489144},
  owner           = {NLM},
  pii             = {CIRCGENETICS.110.958322},
  pmid            = {21252143},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2013-11-21},
}

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