title: Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy.
abstract: BACKGROUND
  Germline genetic variants are an important cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have revealed rare variants in DCM-associated genes also in individuals without known heart disease. In this study, we investigate variant prevalence and genotype-phenotype correlations in Swedish DCM patients, and compare their genetic variants to those detected in reference cohorts.
  
  
  RESULTS
  We sequenced the coding regions of 41 DCM-associated genes in 176 unrelated patients with idiopathic DCM and found 102 protein-altering variants with an allele frequency of <0.04% in reference cohorts; the majority were missense variants not previously described in DCM. Fifty-five (31%) patients had one variant, and 24 (14%) patients had two or more variants in the analysed genes. Detection of genetic variants in any gene, and in LMNA, MYH7 or TTN alone, was associated with early onset disease and reduced transplant-free survival. As expected, nonsense and frameshift variants were more common in DCM patients than in healthy individuals of the reference cohort 1000 Genomes Europeans. Surprisingly however, the prevalence, conservation and pathogenicity scores, and localization of missense variants were similar in DCM patients and healthy reference individuals.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to identify correlations between genotype and prognosis when sequencing a large number of genes in unselected DCM patients. The similar distribution of missense variants in DCM patients and healthy reference individuals questions the pathogenic role of many variants, and suggests that results from genetic testing of DCM patients should be interpreted with caution.
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Dalin
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Pär G
authors.initials: PG
authors.lastname: Engström
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Emil G
authors.initials: EG
authors.lastname: Ivarsson
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Unneberg
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Light
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Schaufelberger
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gilljam
authors.affiliation: Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: bert.andersson@gu.se.
authors.forename: Bert
authors.initials: B
authors.lastname: Andersson
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016019:Survival Analysis; D013548:Sweden; D055815:Young Adult
keywords: Dilated cardiomyopathy; Genetics; Genotype–phenotype correlations; Mutations; Next-generation sequencing