Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

doi:10.1161/CIRCULATIONAHA.120.053033

. 2021 Jul 6;144(1):7-19.

doi: 10.1161/CIRCULATIONAHA.120.053033. Epub 2021 May 5.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

Elizabeth Jordan¹, Laiken Peterson¹, Tomohiko Ai¹, Babken Asatryan², Lucas Bronicki^{3

4}, Emily Brown⁵, Rudy Celeghin⁶, Matthew Edwards⁷, Judy Fan⁸, Jodie Ingles⁹, Cynthia A James⁵, Olga Jarinova^{3

4}, Renee Johnson^{10

11}, Daniel P Judge¹², Najim Lahrouchi¹³, Ronald H Lekanne Deprez¹⁴, R Thomas Lumbers^{15

16

17}, Francesco Mazzarotto^{18

19

20

21}, Argelia Medeiros Domingo²², Rebecca L Miller²³, Ana Morales²⁴, Brittney Murray⁵, Stacey Peters²⁵, Kalliopi Pilichou⁶, Alexandros Protonotarios²⁶, Christopher Semsarian²⁷, Palak Shah²³, Petros Syrris²⁶, Courtney Thaxton²⁸, J Peter van Tintelen²⁹, Roddy Walsh¹³, Jessica Wang⁸, James Ware^{18

19

30}, Ray E Hershberger^{1

31}

Affiliations

¹ Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.
² Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (B.A.).
³ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
⁴ Department of Laboratory and Pathology Medicine, University of Ottawa, Ontario, Canada (L.B., O.J.).
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (E.B., C.A.J., B.M.).
⁶ Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (R.C., K.P.).
⁷ Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom (M.E.).
⁸ Department of Medicine, University of California, Los Angeles (J.F., J. Wang).
⁹ Cardio Genomics Program at Centenary Institute, University of Sydney, Australia (J.I.).
¹⁰ Victor Chang Cardiac Research Institute, Sydney, Australia (R.J.).
¹¹ Department of Medicine, University of New South Wales, Sydney, Australia (R.J.).
¹² Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.P.J.).
¹³ Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, the Netherlands (N.L., R.W.).
¹⁴ Department of Clinical Genetics, Amsterdam University Medical Center location Academic Medical Center, the Netherlands (R.H.L.D.).
¹⁵ Institute of Health Informatics, University College London, London, UK (R.T.L.).
¹⁶ Health Data Research UK London, University College London, UK (R.T.L.).
¹⁷ University College London British Heart Foundation Research Accelerator, London, United Kingdom (R.T.L.).
¹⁸ Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, National Health Service Foundation Trust, London, United Kingdom (F.M., J. Ware).
¹⁹ National Heart and Lung Institute, Imperial College London, United Kingdom (F.M., J. Ware).
²⁰ Department of Clinical and Experimental Medicine, University of Florence, Italy (F.M.).
²¹ Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (F.M.).
²² Swiss DNAlysis Cardiogenetics, Dübendorf, Switzerland (A.M.D.).
²³ Cardiovascular Genomics Center, Inova Heart and Vascular Institute, Falls Church, VA (R.L.M., P. Shah).
²⁴ Invitae Corp, San Francisco, CA (A.M.).
²⁵ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Australia (S.P.).
²⁶ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom (A.P., P. Syrris).
²⁷ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Australia (C.S.).
²⁸ Department of Genetics, University of North Carolina, Chapel Hill (C.T.).
²⁹ Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).
³⁰ Medical Research Council London Institute for Medical Sciences, Imperial College London, United Kingdom (J. Ware).
³¹ Division of Cardiovascular Medicine (R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.

PMID: 33947203
PMCID: PMC8247549
DOI: 10.1161/CIRCULATIONAHA.120.053033

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

Elizabeth Jordan et al. Circulation. 2021.

. 2021 Jul 6;144(1):7-19.

doi: 10.1161/CIRCULATIONAHA.120.053033. Epub 2021 May 5.

Authors

Affiliations

¹ Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.
² Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (B.A.).
³ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
⁴ Department of Laboratory and Pathology Medicine, University of Ottawa, Ontario, Canada (L.B., O.J.).
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (E.B., C.A.J., B.M.).
⁶ Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (R.C., K.P.).
⁷ Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom (M.E.).
⁸ Department of Medicine, University of California, Los Angeles (J.F., J. Wang).
⁹ Cardio Genomics Program at Centenary Institute, University of Sydney, Australia (J.I.).
¹⁰ Victor Chang Cardiac Research Institute, Sydney, Australia (R.J.).
¹¹ Department of Medicine, University of New South Wales, Sydney, Australia (R.J.).
¹² Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.P.J.).
¹³ Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, the Netherlands (N.L., R.W.).
¹⁴ Department of Clinical Genetics, Amsterdam University Medical Center location Academic Medical Center, the Netherlands (R.H.L.D.).
¹⁵ Institute of Health Informatics, University College London, London, UK (R.T.L.).
¹⁶ Health Data Research UK London, University College London, UK (R.T.L.).
¹⁷ University College London British Heart Foundation Research Accelerator, London, United Kingdom (R.T.L.).
¹⁸ Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, National Health Service Foundation Trust, London, United Kingdom (F.M., J. Ware).
¹⁹ National Heart and Lung Institute, Imperial College London, United Kingdom (F.M., J. Ware).
²⁰ Department of Clinical and Experimental Medicine, University of Florence, Italy (F.M.).
²¹ Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (F.M.).
²² Swiss DNAlysis Cardiogenetics, Dübendorf, Switzerland (A.M.D.).
²³ Cardiovascular Genomics Center, Inova Heart and Vascular Institute, Falls Church, VA (R.L.M., P. Shah).
²⁴ Invitae Corp, San Francisco, CA (A.M.).
²⁵ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Australia (S.P.).
²⁶ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom (A.P., P. Syrris).
²⁷ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Australia (C.S.).
²⁸ Department of Genetics, University of North Carolina, Chapel Hill (C.T.).
²⁹ Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).
³⁰ Medical Research Council London Institute for Medical Sciences, Imperial College London, United Kingdom (J. Ware).
³¹ Division of Cardiovascular Medicine (R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.

PMID: 33947203
PMCID: PMC8247549
DOI: 10.1161/CIRCULATIONAHA.120.053033

Abstract

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.

Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.

Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.

Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Keywords: cardiomyopathy; genetics.

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Figures

**Figure 1.**
**Quantitative contributions of genetic and experimental evidence to the clinical validity classifications of genes curated for DCM.** The sums of genetic (blue) and experimental (orange) evidence scores are shown for genes classified as having definitive, strong, moderate, or limited evidence of a monogenic relationship with DCM. The 2 genes noted with an asterisk had quantitative scores within the quantitative range for a moderate classification, but a limited classification was assigned at panel review (see text). DCM indicates dilated cardiomyopathy.

**Figure 2.**
**Genetic architecture of DCM.** The genetic architecture of DCM spans 10 gene ontologies, as shown in the innermost colored text circle. The middle text circle specifies genes classified as strong or definitive (bold text) or moderate (regular text) for DCM, organized by gene ontology. Of the 19 DCM genes shown, 14 have previously been evaluated by other Clinical Genome Resource gene curations for HCM or ARVC and channelopathies, including the long-QT syndrome and Brugada S. Each of these genes has also been classified as moderate, strong, or definitive for these other phenotypes, except for *NEXN*, noted with an asterisk, which has been classified as having limited evidence in HCM. It is expected that with time, as new data emerge that are related to gene-disease relationships in cardiomyopathies and other cardiovascular phenotypes, the structure and orientation of this figure will also evolve. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; Brugada S, Brugada syndrome; Co-Chap, HSP, Co-chaperone, heart shock protein; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; and SR, sarcoplasmic reticulum.

**Figure 3.**
**Curated genes on clinically available DCM genetic testing panels.** The percentages of DCM genetic testing panels that include the genes curated for DCM herein are shown for 16 commercial laboratories identified on the National Center for Biotechnology Information genetic testing registry. Genes are grouped by clinical validity classification, ranging from definitive, strong and moderate (A) to limited, disputed, and no known disease relationship (B). DCM indicates dilated cardiomyopathy.

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Comment in

Reappraising Genes for Dilated Cardiomyopathy: Stepping Back to Move Forward.
Owens AT, Day SM. Owens AT, et al. Circulation. 2021 Jul 6;144(1):20-22. doi: 10.1161/CIRCULATIONAHA.121.054961. Epub 2021 Jul 6. Circulation. 2021. PMID: 34228479 No abstract available.

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References

1. Falk RH, Hershberger RE. Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli G, eds. The dilated, restrictive, and infiltrative cardiomyopathies. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 2018. 11th Edition. Elsevier
1. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med. 1989;321:1372–1378. doi: 10.1056/NEJM198911163212005 - PubMed
1. Graber HL, Unverferth DV, Baker PB, Ryan JM, Baba N, Wooley CF. Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected. Circulation. 1986;74:21–35. doi: 10.1161/01.cir.74.1.21 - PubMed
1. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA, et al. . Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000;36:2226–2233. doi: 10.1016/s0735-1097(00)00997-9 - PubMed
1. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. doi: 10.1016/0092-8674(90)90274-i - PubMed

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[1] Falk RH, Hershberger RE. Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli G, eds. The dilated, restrictive, and infiltrative cardiomyopathies. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 2018. 11th Edition. Elsevier

[2] Falk RH, Hershberger RE. Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli G, eds. The dilated, restrictive, and infiltrative cardiomyopathies. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 2018. 11th Edition. Elsevier

[3] Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med. 1989;321:1372–1378. doi: 10.1056/NEJM198911163212005 - PubMed

[4] Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med. 1989;321:1372–1378. doi: 10.1056/NEJM198911163212005 - PubMed

[5] Graber HL, Unverferth DV, Baker PB, Ryan JM, Baba N, Wooley CF. Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected. Circulation. 1986;74:21–35. doi: 10.1161/01.cir.74.1.21 - PubMed

[6] Graber HL, Unverferth DV, Baker PB, Ryan JM, Baba N, Wooley CF. Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected. Circulation. 1986;74:21–35. doi: 10.1161/01.cir.74.1.21 - PubMed

[7] Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA, et al. . Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000;36:2226–2233. doi: 10.1016/s0735-1097(00)00997-9 - PubMed

[8] Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA, et al. . Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000;36:2226–2233. doi: 10.1016/s0735-1097(00)00997-9 - PubMed

[9] Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. doi: 10.1016/0092-8674(90)90274-i - PubMed

[10] Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. doi: 10.1016/0092-8674(90)90274-i - PubMed

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Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

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Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

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