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Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Author information

1
1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA [3] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
3
1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
4
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
5
1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

PURPOSE:

Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory.

METHODS:

Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses.

RESULTS:

Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%.

CONCLUSION:

Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.

PMID:
24503780
DOI:
10.1038/gim.2013.204
[Indexed for MEDLINE]
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