Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy


Eur Heart J. 2015 Sep 7;36(34):2327-37. doi: 10.1093/eurheartj/ehv253. Epub 2015 Jun 17.

To explore the underlying genetic defects of dilated cardiomyopathy (DCM) we applied OS-Seq technology as a novel comprehensive diagnostic tool. Despite our increasing understanding of the genetics of DCM, the genetic basis of the disease is still poorly understood. We were able to identify pathogenic variants in 47.6% of the cases with family history of DCM and in 25.6% without family history using our Pan Cardiomyopathy Panel in the analysis of 145 Finnish DCM patients. Remarkably, 53% of the significant variants found were titin (TTN) truncations. As the link between titin variants and DCM was established only recently, our study adds substantial evidence and highlights the importance of titin variants underlying DCM. Furthermore, this study showed, once again, that targeted, panel-based sequencing enables high diagnostic yields in a clinical setting.


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.

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.

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.

Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenperä P, Koillinen H, Kaartinen M, Nieminen MS, Myllykangas S, Alastalo TP, Koskenvuo JW, Heliö T.


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Last modified: 11.30.2018