title: Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy.
abstract: OBJECTIVE
  Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool.
  
  
  RESULTS
  Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively.
  
  
  CONCLUSIONS
  Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.
authors.affiliation: Children's Hospital, Institute of Clinical Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Oyediran
authors.initials: O
authors.lastname: Akinrinade
authors.affiliation: Heart and Lung Center HUCH, University of Helsinki, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Ollila
authors.affiliation: Children's Hospital, Institute of Clinical Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Vattulainen
authors.affiliation: Blueprint Genetics, Helsinki, Finland.
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.affiliation: Blueprint Genetics, Helsinki, Finland.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Blueprint Genetics, Helsinki, Finland.
authors.forename: Pertteli
authors.initials: P
authors.lastname: Salmenperä
authors.affiliation: Department of Genetics, University Hospital Helsinki, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Koillinen
authors.affiliation: Heart and Lung Center HUCH, University of Helsinki, Helsinki, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Kaartinen
authors.affiliation: Heart and Lung Center HUCH, University of Helsinki, Helsinki, Finland.
authors.forename: Markku S
authors.initials: MS
authors.lastname: Nieminen
authors.affiliation: Institute of Biomedicine, University of Helsinki, Helsinki, Finland Blueprint Genetics, Helsinki, Finland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Myllykangas
authors.affiliation: Children's Hospital, Institute of Clinical Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Blueprint Genetics, Helsinki, Finland.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.affiliation: Blueprint Genetics, Helsinki, Finland Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland Department of Clinical Physiology and Nuclear Medicine, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, Helsinki 00290, Finland juha.koskenvuo@hus.fi.
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.affiliation: Heart and Lung Center HUCH, University of Helsinki, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Heliö
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D016368:Frameshift Mutation / Q000235:genetics; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D012008:Recurrence
keywords: Diagnosis; Dilated cardiomyopathy; Genetics