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Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 9
2017 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 228, 742-748 p.Article in journal (Refereed) Published
Abstract [en]

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. Methods and 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, MYII7 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. Conclusion: 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.

Place, publisher, year, edition, pages
2017. Vol. 228, 742-748 p.
Keyword [en]
Dilated cardiomyopathy, Genetics, Mutations, Genotype-phenotype correlations, Next-generation sequencing
National Category
Medical Genetics Hematology
Identifiers
URN: urn:nbn:se:su:diva-141364DOI: 10.1016/j.ijcard.2016.11.066ISI: 000393408600117PubMedID: 27886618OAI: oai:DiVA.org:su-141364DiVA: diva2:1092286
Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2017-05-02Bibliographically approved

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Engström, Pär G.Light, Sara
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