Hypertrophic Cardiomyopathy, Genetics & Sudden Death
A genetic history exciting, and tragic, Stacey Burling, The Inquirer, Feb16
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.
Trevor J. Pugh et al. Genetics in Medicine, Feb 7
Trevor J. Pugh et al. Genetics in Medicine, Feb 7
The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: endorsed by the World Heart Federation
Arbustini E, et al. J Am Coll Cardiol 2013 Dec;62(22):2046-72
Arbustini E, et al. J Am Coll Cardiol 2013 Dec;62(22):2046-72
Genetic screening can protect relatives after sudden death, by Dr Philippa Brice, PHG Foundation, Jan 21
Gene Reviews: Hypertrophic Cardiomyopathy Overview. Gene Reviews, by Allison L Cirino and Carolyn Ho (2014)
Clinical utility gene card for: hypertrophic cardiomyopathy (type 1–14)
Yigal M Pinto, et al. Eur J Human Genetics (2011)
Yigal M Pinto, et al. Eur J Human Genetics (2011)
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing
- Trevor J. Pugh PhD,
- Melissa A. Kelly MS,
- Sivakumar Gowrisankar PhD,
- Elizabeth HynesBA,
- Michael A. Seidman MD, PhD,
- Samantha M. Baxter MS,
- Mark Bowser MS,
- Bryan Harrison BA,
- Daniel Aaron BA,
- Lisa M. Mahanta BA,
- Neal K. Lakdawala MD,
- Gregory McDermott BA,
- Emily T. White MS,
- Heidi L. Rehm PhD,
- Matthew Lebo PhD
- & Birgit H. FunkePhD
- Genetics in Medicine
- (2014)
- doi:10.1038/gim.2013.204
- Published online
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.
Genet Med advance online publication 6 February 2014
Keywords:
cardiomyopathy; genetic heterogeneity; molecular diagnostics; next-generation sequencing; variants
No hay comentarios:
Publicar un comentario