Trevor J Pugh1, Melissa A Kelly2, Sivakumar Gowrisankar2, Elizabeth Hynes2, Michael A Seidman3, Samantha M Baxter2, Mark Bowser2, Bryan Harrison2, Daniel Aaron2, Lisa M Mahanta2, Neal K Lakdawala4, Gregory McDermott2, Emily T White2, Heidi L Rehm3, Matthew Lebo3, Birgit H Funke5. 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.
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.
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