title: Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy.
abstract: BACKGROUND
  Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of >50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift toward comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy.
  
  
  RESULTS
  Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1 to 14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and segregation analysis, where available. Three of 3 previously identified primary mutations were detected by this analysis. In 6 subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and had additional pathological correlation to provide evidence for causality. For 2 subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects.
  
  
  CONCLUSIONS
  These pilot data demonstrate that ≈30 to 40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Golbus
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Puckelwartz
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Lisa
authors.initials: L
authors.lastname: Dellefave-Castillo
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: John P
authors.initials: JP
authors.lastname: Fahrenbach
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Viswateja
authors.initials: V
authors.lastname: Nelakuditi
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Lorenzo L
authors.initials: LL
authors.lastname: Pesce
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.affiliation: Department of Medicine, Department of Human Genetics, Department of Pathology, The Computation Institute, The University of Chicago & Argonne National Laboratories, Chicago, IL.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000191:economics / Q000235:genetics; D002648:Child; D030541:Databases, Genetic; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; C509903:MYH11 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D018995:Myosin Heavy Chains
keywords: cardiomyopathies; genetics; genomics; humans