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Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy
AIMS: 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 ol...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561350/ https://www.ncbi.nlm.nih.gov/pubmed/26084686 http://dx.doi.org/10.1093/eurheartj/ehv253 |
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author | Akinrinade, Oyediran Ollila, Laura Vattulainen, Sanna Tallila, Jonna Gentile, Massimiliano Salmenperä, Pertteli Koillinen, Hannele Kaartinen, Maija Nieminen, Markku S. Myllykangas, Samuel Alastalo, Tero-Pekka Koskenvuo, Juha W. Heliö, Tiina |
author_facet | Akinrinade, Oyediran Ollila, Laura Vattulainen, Sanna Tallila, Jonna Gentile, Massimiliano Salmenperä, Pertteli Koillinen, Hannele Kaartinen, Maija Nieminen, Markku S. Myllykangas, Samuel Alastalo, Tero-Pekka Koskenvuo, Juha W. Heliö, Tiina |
author_sort | Akinrinade, Oyediran |
collection | PubMed |
description | AIMS: 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. METHODS AND 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. CONCLUSION: 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. |
format | Online Article Text |
id | pubmed-4561350 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45613502015-09-08 Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy Akinrinade, Oyediran Ollila, Laura Vattulainen, Sanna Tallila, Jonna Gentile, Massimiliano Salmenperä, Pertteli Koillinen, Hannele Kaartinen, Maija Nieminen, Markku S. Myllykangas, Samuel Alastalo, Tero-Pekka Koskenvuo, Juha W. Heliö, Tiina Eur Heart J Basic Science AIMS: 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. METHODS AND 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. CONCLUSION: 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. Oxford University Press 2015-09-07 2015-06-17 /pmc/articles/PMC4561350/ /pubmed/26084686 http://dx.doi.org/10.1093/eurheartj/ehv253 Text en © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Basic Science Akinrinade, Oyediran Ollila, Laura Vattulainen, Sanna Tallila, Jonna Gentile, Massimiliano Salmenperä, Pertteli Koillinen, Hannele Kaartinen, Maija Nieminen, Markku S. Myllykangas, Samuel Alastalo, Tero-Pekka Koskenvuo, Juha W. Heliö, Tiina Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title | Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title_full | Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title_fullStr | Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title_full_unstemmed | Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title_short | Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy |
title_sort | genetics and genotype–phenotype correlations in finnish patients with dilated cardiomyopathy |
topic | Basic Science |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561350/ https://www.ncbi.nlm.nih.gov/pubmed/26084686 http://dx.doi.org/10.1093/eurheartj/ehv253 |
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