Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy
Abstract
Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers ofmore »
- Authors:
-
- Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1280878
- Grant/Contract Number:
- F32 HL097587; T32 HL007237
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Circulation. Cardiovascular genetics
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 6; Journal ID: ISSN 1942-325X
- Publisher:
- American Heart Association
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; cardiomyopathy; genetics; human; genomics; whole genome sequencing
Citation Formats
Golbus, Jessica R., Puckelwartz, Megan J., Dellefave-Castillo, Lisa, Fahrenbach, John P., Nelakuditi, Viswateja, Pesce, Lorenzo L., Pytel, Peter, and McNally, Elizabeth M. Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy. United States: N. p., 2014.
Web. doi:10.1161/circgenetics.113.000578.
Golbus, Jessica R., Puckelwartz, Megan J., Dellefave-Castillo, Lisa, Fahrenbach, John P., Nelakuditi, Viswateja, Pesce, Lorenzo L., Pytel, Peter, & McNally, Elizabeth M. Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy. United States. https://doi.org/10.1161/circgenetics.113.000578
Golbus, Jessica R., Puckelwartz, Megan J., Dellefave-Castillo, Lisa, Fahrenbach, John P., Nelakuditi, Viswateja, Pesce, Lorenzo L., Pytel, Peter, and McNally, Elizabeth M. Mon .
"Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy". United States. https://doi.org/10.1161/circgenetics.113.000578. https://www.osti.gov/servlets/purl/1280878.
@article{osti_1280878,
title = {Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy},
author = {Golbus, Jessica R. and Puckelwartz, Megan J. and Dellefave-Castillo, Lisa and Fahrenbach, John P. and Nelakuditi, Viswateja and Pesce, Lorenzo L. and Pytel, Peter and McNally, Elizabeth M.},
abstractNote = {Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.},
doi = {10.1161/circgenetics.113.000578},
journal = {Circulation. Cardiovascular genetics},
number = 6,
volume = 7,
place = {United States},
year = {Mon Sep 01 00:00:00 EDT 2014},
month = {Mon Sep 01 00:00:00 EDT 2014}
}
Web of Science
Works referenced in this record:
Sodium channel mutations and arrhythmias
journal, May 2009
- Ruan, Yanfei; Liu, Nian; Priori, Silvia G.
- Nature Reviews Cardiology, Vol. 6, Issue 5
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes
journal, August 2005
- Siepel, A.
- Genome Research, Vol. 15, Issue 8
Impaired muscle growth and response to insulin-like growth factor 1 in dysferlin-mediated muscular dystrophy
journal, December 2010
- Demonbreun, Alexis R.; Fahrenbach, John P.; Deveaux, Kieran
- Human Molecular Genetics, Vol. 20, Issue 4
Hypertrophic Cardiomyopathy: Distribution of Disease Genes, Spectrum of Mutations, and Implications for a Molecular Diagnosis Strategy
journal, May 2003
- Richard, Pascale; Charron, Philippe; Carrier, Lucie
- Circulation, Vol. 107, Issue 17
Exome sequencing as a tool for Mendelian disease gene discovery
journal, September 2011
- Bamshad, Michael J.; Ng, Sarah B.; Bigham, Abigail W.
- Nature Reviews Genetics, Vol. 12, Issue 11
Distribution and intensity of constraint in mammalian genomic sequence
journal, June 2005
- Cooper, G. M.
- Genome Research, Vol. 15, Issue 7
Filamin 2 (FLN2): A Muscle-specific Sarcoglycan Interacting Protein
journal, January 2000
- Thompson, Terri G.; Chan, Yiu-Mo; Hack, Andrew A.
- The Journal of Cell Biology, Vol. 148, Issue 1
PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification
journal, January 2003
- Thomas, P. D.
- Nucleic Acids Research, Vol. 31, Issue 1
Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease: MUTATIONS IN BRIEF
journal, March 2005
- Schäfer, Ellen; Baron, Karin; Widmer, Urs
- Human Mutation, Vol. 25, Issue 4
Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing Signals
journal, March 2004
- Yeo, Gene; Burge, Christopher B.
- Journal of Computational Biology, Vol. 11, Issue 2-3
Desmin splice variants causing cardiac and skeletal myopathy
journal, November 2000
- Park, K. -Y.
- Journal of Medical Genetics, Vol. 37, Issue 11
Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly
journal, April 2011
- Chourbagi, Oussama; Bruston, Francine; Carinci, Marianna
- Experimental Cell Research, Vol. 317, Issue 6
Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy
journal, September 2013
- Maerkens, A.; Kley, R. A.; Olivé, M.
- Journal of Proteomics, Vol. 90
Lamin A/C Gene and the Heart
journal, October 2008
- Mestroni, Luisa; Taylor, Matthew R. G.
- Journal of the American College of Cardiology, Vol. 52, Issue 15
A method and server for predicting damaging missense mutations
journal, April 2010
- Adzhubei, Ivan A.; Schmidt, Steffen; Peshkin, Leonid
- Nature Methods, Vol. 7, Issue 4
Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation
journal, January 2005
- Olson, Timothy M.
- JAMA, Vol. 293, Issue 4
Accurate and comprehensive sequencing of personal genomes
journal, July 2011
- Ajay, S. S.; Parker, S. C. J.; Ozel Abaan, H.
- Genome Research, Vol. 21, Issue 9
Filamin C-related myopathies: pathology and mechanisms
journal, October 2012
- Fürst, Dieter O.; Goldfarb, Lev G.; Kley, Rudolf A.
- Acta Neuropathologica, Vol. 125, Issue 1
Myopathies associated with β-tropomyosin mutations
journal, November 2012
- Tajsharghi, H.; Ohlsson, M.; Palm, L.
- Neuromuscular Disorders, Vol. 22, Issue 11
Filamin C plays an essential role in the maintenance of the structural integrity of cardiac and skeletal muscles, revealed by the medaka mutant zacro
journal, January 2012
- Fujita, Misato; Mitsuhashi, Hiroaki; Isogai, Sumio
- Developmental Biology, Vol. 361, Issue 1
Cardiac conduction defects associate with mutations in SCN5A
journal, September 1999
- Schott, Jean-Jacques; Alshinawi, Connie; Kyndt, Florence
- Nature Genetics, Vol. 23, Issue 1
Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy
journal, May 2008
- Hershberger, Ray E.; Parks, Sharie B.; Kushner, Jessica D.
- Clinical and Translational Science, Vol. 1, Issue 1
Accurate whole human genome sequencing using reversible terminator chemistry
journal, November 2008
- Bentley, David R.; Balasubramanian, Shankar; Swerdlow, Harold P.
- Nature, Vol. 456, Issue 7218
ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids
journal, May 2010
- Ashkenazy, H.; Erez, E.; Martz, E.
- Nucleic Acids Research, Vol. 38, Issue Web Server
Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy
journal, February 2002
- Hanson, Emily L.; Jakobs, Petra M.; Keegan, Hugh
- Journal of Cardiac Failure, Vol. 8, Issue 1
Performance comparison of exome DNA sequencing technologies
journal, September 2011
- Clark, Michael J.; Chen, Rui; Lam, Hugo Y. K.
- Nature Biotechnology, Vol. 29, Issue 10
Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy
journal, March 2009
- Maron, Barry J.
- JAMA, Vol. 301, Issue 12
Predicting Deleterious Amino Acid Substitutions
journal, May 2001
- Ng, P. C.; Henikoff, S.
- Genome Research, Vol. 11, Issue 5
The heart in Fabry's disease
journal, January 2011
- Sheppard, Mary N.
- Cardiovascular Pathology, Vol. 20, Issue 1
Comprehensive comparison of three commercial human whole-exome capture platforms
journal, January 2011
- Asan, ; Xu, Yu; Jiang, Hui
- Genome Biology, Vol. 12, Issue 9, p. R95
Genetic Testing for Inherited Heart Disease
journal, July 2013
- Cirino, Allison L.; Ho, Carolyn Y.
- Circulation, Vol. 128, Issue 1
Subtle Abnormalities in Contractile Function Are an Early Manifestation of Sarcomere Mutations in Dilated Cardiomyopathy
journal, October 2012
- Lakdawala, Neal K.; Thune, Jens J.; Colan, Steven D.
- Circulation: Cardiovascular Genetics, Vol. 5, Issue 5
A novel custom resequencing array for dilated cardiomyopathy
journal, May 2010
- Zimmerman, Rebekah S.; Cox, Stephanie; Lakdawala, Neal K.
- Genetics in Medicine, Vol. 12, Issue 5
Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies
journal, April 2011
- Meder, Benjamin; Haas, Jan; Keller, Andreas
- Circulation: Cardiovascular Genetics, Vol. 4, Issue 2
Truncations of Titin Causing Dilated Cardiomyopathy
journal, February 2012
- Herman, Daniel S.; Lam, Lien; Taylor, Matthew R. G.
- New England Journal of Medicine, Vol. 366, Issue 7
Population-Based Variation in Cardiomyopathy Genes
journal, August 2012
- Golbus, Jessica R.; Puckelwartz, Megan J.; Fahrenbach, John P.
- Circulation: Cardiovascular Genetics, Vol. 5, Issue 4
Desmin Myopathy, a Skeletal Myopathy with Cardiomyopathy Caused by Mutations in the Desmin Gene
journal, March 2000
- Dalakas, Marinos C.; Park, Kye-Yoon; Semino-Mora, Cristina
- New England Journal of Medicine, Vol. 342, Issue 11
Mutational Analysis of Fukutin Gene in Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy
journal, January 2009
- Arimura, Takuro; Hayashi, Yukiko K.; Murakami, Terumi
- Circulation Journal, Vol. 73, Issue 1
Smooth muscle myosin heavy chain isoforms and their role in muscle physiology
journal, January 2000
- Babu, Gopal J.; Warshaw, David M.; Periasamy, Muthu
- Microscopy Research and Technique, Vol. 50, Issue 6
Desminopathies: pathology and mechanisms
journal, November 2012
- Clemen, Christoph S.; Herrmann, Harald; Strelkov, Sergei V.
- Acta Neuropathologica, Vol. 125, Issue 1
Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients With Dilated Cardiomyopathy
journal, August 2009
- Hershberger, Ray E.; Pinto, Jose Renato; Parks, Sharie B.
- Circulation: Cardiovascular Genetics, Vol. 2, Issue 4
Effects of enzyme replacement therapy in Fabry disease—A comprehensive review of the medical literature
journal, October 2010
- Lidove, Olivier; West, Michael L.; Pintos-Morell, Guillem
- Genetics in Medicine, Vol. 12, Issue 11
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing
journal, February 2021
- Yan, Huifang; Ji, Haoran; Kubisiak, Thomas
- Journal of Human Genetics, Vol. 66, Issue 8
Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus)
journal, November 2020
- Samaha, Georgina; Wade, Claire M.; Beatty, Julia
- Scientific Reports, Vol. 10, Issue 1
FASTA/Q data compressors for MapReduce-Hadoop genomics: space and time savings made easy
journal, March 2021
- Ferraro Petrillo, Umberto; Palini, Francesco; Cattaneo, Giuseppe
- BMC Bioinformatics, Vol. 22, Issue 1
Stairway Plot 2: demographic history inference with folded SNP frequency spectra
journal, November 2020
- Liu, Xiaoming; Fu, Yun-Xin
- Genome Biology, Vol. 21, Issue 1
Hypertrophic Cardiomyopathy
book, January 2018
- Shanmugasundaram, S.; Vinodkumar, B.; Rajeswari, K.
- Textbook of Echocardiography
A map of human genome variation from population-scale sequencing
text, January 2010
- Yun, Li,
- The University of North Carolina at Chapel Hill University Libraries
Hypertrophic Cardiomyopathy
journal, September 2011
- Pinckard, J. Keith
- Academic Forensic Pathology, Vol. 1, Issue 2
Works referencing / citing this record:
Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy
journal, October 2018
- Schubert, Jeffrey; Tariq, Muhammad; Geddes, Gabrielle
- Human Mutation, Vol. 39, Issue 12
A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients
journal, October 2017
- Cirino, Allison L.; Lakdawala, Neal K.; McDonough, Barbara
- Circulation: Cardiovascular Genetics, Vol. 10, Issue 5
Dilated cardiomyopathy
journal, February 2010
- Jefferies, John Lynn; Towbin, Jeffrey A.
- The Lancet, Vol. 375, Issue 9716
Targeted next-generation sequencing detects novel gene–phenotype associations and expands the mutational spectrum in cardiomyopathies
journal, July 2017
- Forleo, Cinzia; D’Erchia, Anna Maria; Sorrentino, Sandro
- PLOS ONE, Vol. 12, Issue 7
Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy
journal, December 2015
- Long, Pamela A.; Larsen, Brandon T.; Evans, Jared M.
- Journal of the American Heart Association, Vol. 4, Issue 12
Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy
journal, November 2018
- Cui, Hao; Wang, Jizheng; Zhang, Ce
- Molecular Genetics & Genomic Medicine, Vol. 6, Issue 6
Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy
journal, March 2018
- Herkert, Johanna C.; Abbott, Kristin M.; Birnie, Erwin
- Genetics in Medicine, Vol. 20, Issue 11
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
posted_content, February 2016
- Walsh, Roddy; Thomson, Kate L.; Ware, James S.
- bioRxiv
Next Generation Sequencing Methods for Diagnosis of Epilepsy Syndromes
journal, February 2018
- Dunn, Paul; Albury, Cassie L.; Maksemous, Neven
- Frontiers in Genetics, Vol. 9
Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients
journal, April 2017
- Gómez, Juan; Lorca, Rebeca; Reguero, Julian R.
- Circulation: Cardiovascular Genetics, Vol. 10, Issue 2
Molecular insights into cardiomyopathies associated with desmin (DES) mutations
journal, June 2018
- Brodehl, Andreas; Gaertner-Rommel, Anna; Milting, Hendrik
- Biophysical Reviews, Vol. 10, Issue 4
Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy
journal, January 2016
- Brodehl, Andreas; Ferrier, Raechel A.; Hamilton, Sara J.
- Human Mutation, Vol. 37, Issue 3
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
journal, August 2016
- Walsh, Roddy; Thomson, Kate L.; Ware, James S.
- Genetics in Medicine, Vol. 19, Issue 2
Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield
journal, December 2018
- Thomson, Kate L.; Ormondroyd, Elizabeth; Harper, Andrew R.
- Genetics in Medicine, Vol. 21, Issue 7
The Role of Genetic Testing in the Identification of Young Athletes with Inherited Primitive Cardiac Disorders at Risk of Exercise Sudden Death
journal, August 2016
- Tiziano, Francesco Danilo; Palmieri, Vincenzo; Genuardi, Maurizio
- Frontiers in Cardiovascular Medicine, Vol. 3
Translating emerging molecular genetic insights into clinical practice in inherited cardiomyopathies.
text, January 2018
- Asatryan, Babken; Medeiros-Domingo, Argelia
- Springer
Heart Failure: Diagnosis, Evaluation
book, January 2008
- Chen, Horng
- Mayo Clinic Cardiology Concise Textbook and Mayo Clinic Cardiology Board Review Questions & Answers
Dilated cardiomyopathy: experimental aspects
journal, January 1987
- Abelmann, W. H.
- Current Opinion in Cardiology, Vol. 2, Issue 3
Dilated Cardiomyopathy
book, September 2018
- Cunningham, Suzanne M.; Pierce, Kursten V.
- Textbook of Small Animal Emergency Medicine
Translating emerging molecular genetic insights into clinical practice in inherited cardiomyopathies
journal, August 2018
- Asatryan, Babken; Medeiros-Domingo, Argelia
- Journal of Molecular Medicine, Vol. 96, Issue 10
Dilated Cardiomyopathy: Genetic Determinants and Mechanisms
journal, September 2017
- McNally, Elizabeth M.; Mestroni, Luisa
- Circulation Research, Vol. 121, Issue 7
Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy
journal, November 2018
- Cui, Hao; Wang, Jizheng; Zhang, Ce
- Molecular Genetics & Genomic Medicine, Vol. 6, Issue 6
The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure
journal, February 2015
- McNally, Elizabeth M.; Barefield, David Y.; Puckelwartz, Megan J.
- Cell Metabolism, Vol. 21, Issue 2
FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy
journal, August 2016
- Begay, Rene L.; Tharp, Charles A.; Martin, August
- JACC: Basic to Translational Science, Vol. 1, Issue 5
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
posted_content, February 2016
- Walsh, Roddy; Thomson, Kate L.; Ware, James S.
- bioRxiv
Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy
journal, December 2015
- Long, Pamela A.; Larsen, Brandon T.; Evans, Jared M.
- Journal of the American Heart Association, Vol. 4, Issue 12
High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation
journal, December 2017
- Klauke, Baerbel; Gaertner-Rommel, Anna; Schulz, Uwe
- PLOS ONE, Vol. 12, Issue 12
The Role of Genetic Testing in the Identification of Young Athletes with Inherited Primitive Cardiac Disorders at Risk of Exercise Sudden Death
journal, August 2016
- Tiziano, Francesco Danilo; Palmieri, Vincenzo; Genuardi, Maurizio
- Frontiers in Cardiovascular Medicine, Vol. 3