REVIEwS

Genetics of dilated cardiomyopathy:

practical implications for heart failure
management
Andrew N. Rosenbaum   1, Katherine E. Agre   2 and Naveen L. Pereira1,3,4*
Abstract | Given the global burden of heart failure, strategies to understand the underlying
cause or to provide prognostic information are critical to reducing the morbidity and mortality
associated with this highly prevalent disease. Cardiomyopathies often have a genetic cause,
and the field of heart failure genetics is progressing rapidly. Through a deliberate investigation,
evaluation for a familial component of cardiomyopathy can lead to increased identification of
pathogenic genetic variants. Much research has also been focused on identifying markers of risk
in patients with cardiomyopathy with the use of genetic testing. Advances in our understanding
of genetic variants have been slightly offset by an increased recognition of the heterogeneity of
disease expression. Greater breadth of genetic testing can increase the likelihood of identifying a
variant of uncertain significance, which is resolved only rarely by cellular functional validation and
segregation analysis. To increase the use of genetics in heart failure clinics, increased availability
of genetic counsellors and other providers with experience in genetics is necessary. Ultimately,
through ongoing research and increased clinical experience in cardiomyopathy genetics, an
improved understanding of the disease processes will facilitate better clinical decision-​making
about the therapies offered, exemplifying the implementation of precision medicine.

1
Department of
Cardiovascular Medicine,
Mayo Clinic, Rochester,
MN, USA.
2
Department of Clinical
Genomics, Mayo Clinic,
Rochester, MN, USA.
3
William J. von Liebig Center
for Transplantation and
Clinical Regeneration, Mayo
Clinic, Rochester, MN, USA.
4
Department of Molecular
Pharmacology and
Experimental Therapeutics,
Mayo Clinic, Rochester,
MN, USA.
*e-​mail: pereira.naveen@
mayo.edu
https://doi.org/10.1038/
s41569-019-0284-0
The global prevalence of heart failure is approximately
26 million patients, and the current estimates of the
incidence and prevalence of heart failure in the USA are
nearly 1 million per year and >6 million patients, respec-
tively1–3. Although some marginal declines in the inci-
dence of heart failure can be attributed to a reduction in
risk factors for cardiovascular disease and improvements
in management, the need to identify and treat heart
failure is growing, particularly given an overall 5-year
survival of only 50% after diagnosis of heart failure4.
The global economic burden related to heart failure is
approximately US$120 billion3 and, in the USA, $30 bil-
lion of spending per year is estimated to be attributable
to direct and indirect costs resulting from heart failure
care5. The large burden of this disease means that devel-
oping effective management strategies is paramount.
Dilated cardiomyopathy (DCM) is the second most
common cause of heart failure (after coronary artery
disease), underlying approximately 36% of all heart fail-
ure cases, and has an estimated prevalence of >0.4% in
the general population6–8. Of these patients, 25–30% are
estimated to have an identifiable familial component (as
defined below)7,9–13.
In this Review, we give a broad perspective on
the genetic causes of DCM to provide a context for a
discussion of the pragmatic use of genetic testing in
heart failure clinics for patients presenting with new-​
onset cardiomyopathy. We aim to provide clinicians with
a focused, evidence-​based guide to the use of genetic
testing to facilitate the management of genetic cardio­
myopathies. An extensive overview of the molecular
mechanisms and pathogenesis of DCM is not provided,
nor is a comprehensive summary of all the genetic vari-
ants that have been identified, but these areas have been
reviewed previously14–16.
Background
Defining idiopathic and familial DCM
Although generally straightforward in clinical practice,
the diagnostic criteria for cardiomyopathies are important
to consider in the context of applying appropriate genetic
considerations to the diagnostic work-​up. DCM is gener-
ally defined as a left ventricular ejection fraction (LVEF)
of <45%, with a left ventricular end-​diastolic dimension
>112% of that predicted for age and body surface area17.
The term ‘idiopathic’ can be applied only after exclusion
of the vast array of potential causes, many of which require
simple, non-​invasive tests and, increasingly, the use of
cardiac MRI, with an emphasis on the clinical history18.
Familial DCM is diagnosed when two or more family

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can have a higher or lower yield. For example, a genetic

Key points
cause of hypertrophic cardiomyopathy (HCM) can be
• The frontier of genetics is rapidly advancing and, increasingly, genetic testing in heart identified in ≥50% of patients on the basis of the pres-
failure clinics is associated with benefit for family screening and individual ence of various clinical factors7. As in HCM, identify-
prognostication. ing the genetic cause of DCM can provide substantial
• A focused evaluation of the clinical characteristics and inheritance pattern of heart clinical insight into family screening, management and
failure or sudden cardiac death, in addition to consultation with a genetic counsellor prognosis29,30. However, other cardiomyopathies, such as
when appropriate, can facilitate a successful genetic evaluation.
restrictive or noncompaction cardiomyopathy, are less
• Genetic testing is recommended in all patients with familial dilated cardiomyopathy well described and might have a lower degree of famil-
(DCM) to facilitate screening, whereas guideline recommendations for testing in
ial involvement and a variable rate of identification of
patients with sporadic DCM differ, but specific clinical features might increase the
the pathogenic variant, which might partly be caused
yield of testing.
by differences in the interpretation or diagnosis of the
• Genetic testing in DCM is currently associated with the identification of a culprit
phenotype31–34.
variant in approximately 15–25% of patients with sporadic DCM and approximately
20–40% of patients with familial DCM.
Genetic aetiology in heart failure
• The identification of a pathogenic variant might have important predictive and
therapeutic implications; however, expression of the phenotype might depend on A targeted, three-​generation family history is of the
environmental triggers. utmost importance when one is assessing whether car-
• All first-​degree relatives of patients with familial DCM should undergo clinical
diomyopathy is sporadic or familial. In this Review, we
screening; guidelines for screening of first-​degree relatives of patients with sporadic use the term ‘sporadic’ to refer to any proband without a
DCM differ. family history of phenotypic manifestation of the disease
(more precisely termed ‘simplex’)7. The family history
also provides data on the likelihood of identifying a
members meet the criteria for DCM or when the patient genetic cause and is critical to evaluating the possibility
of interest (proband) meets the criteria for DCM and a of a syndromic association35. Table 2 provides a list of
first-​degree relative has experienced sudden cardiac death some common syndromic causes of DCM, with clinical
aged <35 years19. However, these definitions are arbitrary phenotype–gene correlations. Ascertainment of a ped-
and often difficult to document conclusively. In general, igree with phenotypic traits allows strategies for testing
familial DCM should be suspected when family members and for the evaluation of relatives to be determined36,37.
of the proband have been reported to have heart failure or Important elements of a family history include the
premature sudden cardiac death without a well-​defined age of relatives, health status, cardiac screening status of
cause. In addition, if left ventricular dilatation without a first-​degree relatives and cause of death (when applicable),
reduction in LVEF is detected during screening of first-​ with appropriate subsequent questions, particularly in the
degree family members, a diagnosis of familial DCM setting of red flags (Box 1). Furthermore, ascertainment of
should also be considered. ancestral background and the presence of consanguinity
is important because these factors affect the frequency of
Frequency of genetic variants potentially disease-​causing recessive alleles. Reviewing
A variant in the genome that has a ≥90% likelihood of death certificates and autopsy reports can provide further
causing DCM is referred to as a pathogenic or likely path- and more accurate insights into the cause of death.
ogenic genetic variant20. In contrast to many Mendelian Suspicion of familial cardiomyopathy should be high
disorders, genetic associations present in familial cardio­ in scenarios in which a family has more than one
myopathies have variable penetrance, and manifes- affected individual and in which a family member has
tations might occasionally be observed only when experienced sudden cardiac death. However, potential
exposure to an additional insult occurs21,22. Furthermore, limitations to the pedigree approach must be acknowl-
estimates of a genetic cause of DCM are solely on the edged, which include a lack of family history data, lim-
basis of well-​characterized known pathogenic or likely ited family structure and incomplete family cardiac
pathogenic genetic variants that have been identified screening.
so far; many more culprit genetic variants are likely to Elucidating a heritable link between family members
exist23,24. Nevertheless, estimates of the frequency of of a patient with cardiomyopathy can be difficult because of
underlying pathogenic variants range from 15% to 25% in incomplete penetrance and variable expressivity (such as
unselected patients with DCM and from 20% to 40% asymptomatic ventricular dysfunction and/or dilatation,
in patients with familial DCM25–28. Table 1 details the manifestations due to conduction tissue disease, heart
ten genes that have been most commonly implicated failure and the particularly challenging occurrence of sud-
in DCM and their estimated frequency in non-​syndromic den cardiac death)13,38. Subclinical or early clinical disease
DCM. Figure 1 shows the location in a cardiomyocyte that might not be apparent from the family history could
of the proteins encoded by these ten genes. Of note, be present in up to 29% of affected families39.
the likelihood of identifying a culprit genetic vari-
ant (the ‘yield’) is higher in syndromic DCM than in Genetics in the management of DCM
non-​syndromic DCM, particularly in those patients Clinical guidelines
with coexistent muscular dystrophies,  conduction Clinical guidelines have assisted clinicians in determin-
defects or hearing loss13. ing when to use genetic testing to aid in the diagnosis and
Compared with genetic testing in patients with DCM, management of idiopathic DCM. Each guideline empha-
genetic testing in patients with other cardiomyopathies sizes a thorough family history and physical examination

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Table 1 | Top ten genes in which dCM-​associated variants most commonly occur7,28,35
gene (protein) Protein Estimated age of onset of dCM associated Notes ref.
function prevalence in (years) disorders
dCM (%)
TTN (titin) Sarcomere, 12–25a Usually 40–59 Usually isolated More common in women than 54

structural DCM in men; variable prognosis but

family clustering
LMNA (lamin A/C) Nuclear 4–6 (up to 30 30–49; conduction Subset of Emery– Most conduction disease 46

membrane if conduction disease usually Dreifuss muscular cases symptomatic over time;
disease also prominent dystrophy ventricular arrhythmias common
present)
MYH7 (β-​myosin Sarcomere 4–10a Variable: adolescence Primarily HCM; Prognosis variable depending 64

heavy chain) to 49 also LVNC and on site of genetic variant;

RCM homogeneity within families
MYH6 (α-​myosin Sarcomere 4 Variable: adolescence Primarily HCM Prognosis variable depending 64

heavy chain) to 49 on site of genetic variant;

homogeneity within families
MYPN (myopalladin) Sarcomere, 3–4 Variable: adolescence Usually isolated Variable presentation with some 70

Z-​disc to 59 DCM early deaths due to heart failure

DSP (desmoplakin) Desmosome 3–4 40–49 ARVC Identified in multiple patients 79

with advanced DCM although

natural history uncertain;
arrhythmic burden seems to be
much lower than in ARVC
RBM20 (RNA-​binding RNA-​binding 2–5 Adolescence to 39; can Usually isolated Rapid progression: SCD and 84

protein 20) protein, present with SCD or DCM end-​stage heart failure are
spliceosome advanced heart failure common, with a high incidence
of ventricular arrhythmias
TNNT2 (cardiac Sarcomere 2–3 Variable: adolescence HCM, LVNC and Prognosis variable depending 64

muscle troponin T) to 49 RCM on site of genetic variant;

homogeneity within families
SCN5A (sodium Ion channel 2–3 Adolescence Brugada syndrome Early onset, commonly with atrial 87

channel protein type and LQTS fibrillation; not associated with

5, α subunit) risk of ventricular arrhythmias
TPM1 Sarcomere 0.5–1.0 Variable: adolescence HCM, LVNC and Prognosis variable depending 64

(α-​tropomyosin) to 49 RCM on site of genetic variant;

homogeneity within families
ARVC, arrhythmogenic right ventricular cardiomyopathy ; DCM, dilated cardiomyopathy ; HCM, hypertrophic cardiomyopathy ; LQTS, long QT syndrome; LVNC;
left ventricular noncompaction cardiomyopathy ; RCM, restrictive cardiomyopathy ; SCD, sudden cardiac death. aHigher end of the range if DCM is familial.

in patients with DCM and appropriate screening of
first-​degree family members of affected patients.
Regarding screening for familial DCM, the 2013
ACC/AHA heart failure guidelines40, the 2009 Heart
Failure Society of America (HFSA) guidelines29 (which
were updated in 2018 in a joint publication with the
American College of Medical Genetics (ACMG)25),
the 2010 ESC guidelines for genetic testing and counsel-
ling41 and the 2016 AHA scientific statement on DCM42
recommend clinical screening of adult first-​degree rela­
tives of affected individuals, with electrocardiographic
and echocardiographic examination of left ventricular
function and size every 3–5 years. Additionally, accord-
ing to a 2011 joint expert consensus statement from
the Heart Rhythm Society (HRS) and European Heart
Rhythm Association (EHRA)43, if a pathogenic or likely
pathogenic variant is present in a proband, cascade
screening should be conducted; this recommendation
is supported by the guidelines from the ACMG, ESC
and AHA25,41,42. If a family member undergoes genetic
screening and a pathogenic variant is identified in the
absence of phenotypic manifestations, both the 2018
HFSA guidelines and the 2010 ESC guidelines indicate
that interval screening should occur for phenotypic
manifestations, in addition to appropriate disease
counselling25,41. In the absence of a family history or an
identifiable pathogenic genetic variant, the ACC/AHA
guidelines recommend that clinical screening of fam-
ily members of patients with sporadic idiopathic DCM
should be left to the discretion of the family members’
physicians and is not routinely recommended40. The
AHA scientific statement on DCM similarly indicates
that clinical screening of first-​degree relatives might be
reasonable42. However, because of uncertainties about
the distinction between familial and sporadic cardiomy-
opathies, the ESC recommends routine clinical screen-
ing in all first-​degree relatives of patients with DCM if
genetic information is unavailable41.
Regarding genetic testing in familial DCM specifi-
cally, the updated 2018 HFSA/ACMG guidelines and
the 2010 ESC guidelines recommend testing of the most
affected family member25,41. The 2013 ACC/AHA guide-
lines and the 2016 AHA scientific statement indicate that
genetic testing can be considered together with genetic
counselling, although specific recommendations about
whom to test are not given40,42.

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Sodium channel
protein type 5 (SCN5A)
Plasma membrane
Cytoplasm
Myosin heavy chain Cardiac muscle α-Tropomyosin
Titin (TTN) (MYH6 and MYH7) troponin T (TNNT2) (TPM1)
Myopalladin Z-disc
(MYPN)
Nucleus Lamin A/C
(LMNA)
Desmoplakin
(DSP)
RNA-binding
protein 20 (RBM20)
Desmosome Mitochondrion
Fig. 1 | Cellular locations of proteins associated with dCM. The graphic shows the
approximate cellular locations of the ten proteins and their respective genes in which
dilated cardiomyopathy (DCM)-causing pathogenic variants most commonly occur
(see Table 1).
The guidelines differ somewhat with respect to spo-
radic DCM (in the absence of a family history of the
disease) largely because of the unknown diagnostic yield
and clinical utility of genetic screening in this popu­
lation. The ESC and ACC/AHA guidelines emphasize
that, unless particular clinical features (a family history
of cardiac conduction disease, premature sudden cardiac
death or the recommendation of particular therapies)
are present, routine genetic testing is not systematically
recommended40,41, whereas the HFSA/ACMG guidelines
recommend that genetic testing can facilitate cascade
screening and should be performed in all patients with
DCM25. The HRS/EHRA guidelines recommend testing
in patients with DCM and clinically significant cardiac
conduction disease or a family history of premature,
unexpected death43.
As a result of publications describing a new pheno-
typic paradigm of arrhythmogenic cardiomyopathy,
emphasizing the substantial overlap between DCM,
arrhythmogenic cardiomyopathy and heritable arrhyth-
mia syndromes, the HRS has released an updated con-
sensus document44 to address comprehensively the
unique electrophysiological considerations (including
mechanisms, implantable cardioverter–defibrillator
therapy and management of dysrhythmia) as well as gen-
eral management of cardiomyopathies with arrhythmia
as a prominent component.
Genetic variants causing DCM
Laminopathies. Lamin A/C is a nuclear envelope protein
encoded by LMNA that functions as a support element,
with a structure homologous to that of intermediate fil-
aments. The pathogenesis of LMNA-​associated DCM
involves disruption of chromatin organization in divid-
ing cells and of signal transduction in non-​dividing
cells45,46. LMNA variants most commonly result in both
DCM and conduction system disease, with the for-
mer generally occurring in the fourth to fifth decade
of life, eventually requiring pacing in most patients46.
Additionally, the risk of sudden cardiac death is high
(up to 46%) in patients with LMNA variants compared
with controls (OR 3.7, 95% CI 2.3–5.9, P < 0.001), and
many patients require pacemaker implantation47.
The prevalence of LMNA variants as a cause of DCM
is not definitively known, but general estimates range
from 4% to 8%28,46,48. In a highly selected population
of tertiary referral patients with familial DCM, LMNA
variants were identified in 30% of those presenting with
DCM and conduction system disease, in 88% of those
presenting with DCM and a muscular dystrophy syn-
drome and even in 25% of those presenting with isolated
conduction system disease without DCM49.
Sarcomeric protein cardiomyopathies. Variants in
genes that encode sarcomeric proteins, which are
involved in contractile force generation and cellular
anchoring, underlie a range of cardiomyopathies, from
hypertrophic remodelling to ventricular dilatation, and
phenotypic variability is common50. Variants in some
genes encoding sarcomeric proteins that are associated
with DCM might exert their effect through impaired
responses to physiological stress51,52. The sarcomeric
protein of greatest attention in the context of DCM is
titin, encoded by TTN. Several types of variants in TTN
that cause truncation of the protein have been identi-
fied53. Variants in TTN might cause up to 25% of cases
of familial DCM, inherited in an autosomal-​dominant
manner, and 12–18% of cases of sporadic DCM54,55.
Variants in TTN are not generally associated with car-
diac conduction defects or skeletal muscle disease53,54.
The presentation of titin cardiomyopathy is generally
similar to that of idiopathic forms of DCM, with onset
in the fifth to sixth decade of life55. Prognosis is also
similar, but patients with titin cardiomyopathy might
have a better response to medical therapy than those
with idiopathic DCM56.
Putative pathogenic variants have also been identified
in genes encoding proteins involved in the sarcomeric
contractile apparatus, namely (in order of prevalence)
MYH7 (encoding myosin 7, also known as β-myosin
heavy chain), MYH6 (encoding myosin 6, also known
as α-​myosin heavy chain), TNNT2 (encoding cardiac
muscle troponin T), MYBPC3 (encoding cardiac-​type
myosin-​binding protein C), TNNI3 (encoding cardiac
muscle troponin I), TPM1 (encoding α-​tropomyosin),
MYL2 (encoding myosin regulatory light chain 2), MYL3
(encoding myosin light chain 3) and ACTC1 (encoding
α-​cardiac actin)50,57–60. More frequently identified in
HCM, MYBPC3 variants constitute 30–40% of HCM
pathogenic variants, and MYH7 variants constitute
20–30% of HCM pathogenic variants57,61–63. However,
variants in these genes have also been discovered to con-
tribute to DCM, with phenotypic heterogeneity driven
by mutation locus64,65. The proportion of familial DCM
that results from variants in genes that encode contrac-
tile proteins might be as high as 10%, with substantial
phenotypic heterogeneity64.
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Variants also occur in genes encoding proteins of the
Z-​disc, which can similarly result in DCM phenotypes.
DCM-​causing variants have been identified in ACTN2
(encoding α-​actinin 2), ANKRD1 (encoding ankyrin
repeat domain-​containing protein 1), CSRP3 (encoding
muscle LIM protein), LDB3 (encoding LIM domain-​
binding protein 3), MYOZ2 (encoding myozenin 2),
TCAP (encoding telethonin) and VCL (encoding vin-
culin)66–69. Variants in MYPN, encoding myopalladin,
another important Z-​disc-associated protein with struc-
tural and signalling functions, were found to occur in
European patients with DCM at a frequency of 3–4%70.
Myofibrillar cardiomyopathy. Beyond the sarcomere
unit, intermediate filaments maintain the structural
integrity of the myofibril, allow force generation and
facilitate signalling. The main intermediate filament
protein in both cardiomyocytes and skeletal myocytes
is desmin, encoded by DES71. Variants in DES are gen-
erally inherited in an autosomal-​dominant fashion and
characteristically present with conduction defects caus-
ing syncopal events or even sudden cardiac death71,72.
DES variants have also been associated with restrictive
cardiomyopathy, with a characteristic presentation of
concomitant atrioventricular block73.
Pathogenic variants in FLNC, encoding another
structural protein, filamin C, were previously thought to
affect both skeletal and cardiac muscle, but research has
now confirmed a cardiac-​specific, DCM phenotype74.
Pathogenic variants in FLNC are often highly pene-
trant and associated with a high risk of sudden cardiac
death75,76. Guidelines give a class IIa recommendation for
cardioverter–defibrillator implantation if a pathogenic
FLNC variant is present and the LVEF is <45%44.
Another cause of myofibrillar cardiomyopathy is var-
iants in BAG3, which encodes an intracellular chaperone
protein. In a severe phenotype, BAG3 variants result in
severe muscular dystrophy in children77.
Desmosomal cardiomyopathy. Desmosomes are pro-
teins involved in the structure and function of the
intercalated discs, which are important for transmis-
sion of electrical activity from cell to cell and also have
Table 2 | dCM clinical phenotype–gene associations
distinguishing clinical features of dCM at Suspected variant gene
presentation or syndrome
DCM with prominent conduction disease LMNA
DCM or restrictive cardiomyopathy with conduction DES or LMNA
disease or sudden cardiac death and skeletal myopathy
Early-​onset, rapidly progressive DCM with ventricular RBM20
arrhythmias
Early-​onset DCM with history of muscular dystrophy DMD
Early-​onset, rapidly progressive DCM with X-​linked DMD (X-​linked DCM)
inheritance pattern, without muscular dystrophy
Ophthalmoplegia, conduction defects and DCM Kearns–Sayre syndrome
(mitochondrial)
Myoclonic epilepsy , septal hypertrophy and DCM MERRF syndrome
(mitochondrial)
DCM, dilated cardiomyopathy ; MERRF, myoclonus epilepsy with ragged red fibres.
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mechanical and signalling functions. Variants in genes
encoding desmosomal proteins are traditionally associ-
ated with arrhythmogenic right ventricular cardiomyop­
athy. However, left ventricular dysfunction can occur in a
DCM pattern independently of right ventricular involve-
ment and, therefore, the true pathogenesis of arrhythmo-
genic right ventricular cardiomyopathy or DCM
secondary to variants in genes encoding desmoso­mal
proteins is incompletely understood78.
The major culprit variants for DCM seem to be
located in the desmosomal genes DSP (encoding desmo-
plakin) and PKP2 (encoding plakophilin 2). Pathogenic
variants in these genes might be under-​recognized.
One report described a prevalence of 13% for patho-
genic variants in genes encoding desmosomal proteins
among unselected patients undergoing cardiac trans-
plantation for idiopathic DCM79, whereas other studies
of unselected patients with isolated DCM have identified
DSP as being the fourth most common gene to have
DCM-​causing variants28.
Tafazzin-​related cardiomyopathy. Variants in TAZ (also
known as G4.5), which encodes a variety of proteins
involved in the regulation of cardiolipin, namely the taf-
azzin proteins, can cause Barth syndrome (features of
which include DCM, short stature, lactic acidosis and neu-
tropenia) in infants80,81. However, other variants in TAZ
can result in a less severe phenotype of DCM. Variants in
DTNA, encoding dystrobrevin-​α, might cause an X-​linked,
noncompaction cardiomyopathy phenotype80,82,83.
Other genetic variants associated with cardiomyopathies.
Several other genetic variants have been associated with
DCM, with diverse pathogenic mechanisms. Variants in
RBM20, which encodes RNA-​binding protein 20, which is
involved in providing mRNA post-​transcriptional modifi-
cations in spliceosomes, were identified in 2009 as a cause
of DCM84. Rapid progression towards advanced heart fail-
ure is not uncommon by the fourth decade of life, and the
occurrence of ventricular arrhythmias and sudden cardiac
death is high in patients with RBM20 variants84,85.
Variants in SCN5A, encoding the α-​subunit of the
cardiac sodium channel, are typically associated with
Brugada syndrome or long QT syndrome but might
also increase the propensity for heart failure86. The
DCM phenotype of individuals with SCN5A variants can
include conduction disturbance and arrhythmias86. The
age of onset of cardiomyopathy associated with SCN5A
variants is early, in the second to third decade of life87.
Important syndromic DCMs
Mitochondrial myopathies. An extensive range of car-
diomyopathies are associated with mitochondrial disor-
ders. Mitochondrial myopathies display two inheritance
patterns: maternal transmission (owing to segregation
of mitochondria in dividing cells) and autosomal dom-
inant (because some nuclear proteins also interact with
mitochondria and can cause disease)88. Genetic testing for
mitochondrial myopathies relies on gene sequencing
of mitochondrial DNA for known pathogenic variants;
unlike with nuclear genes, phenotypic expression of vari-
ants in mitochondrial genes is proportional to the number
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Box 1 | Family history red flags
Any of the following findings in the family history should prompt further investigation:
• Sudden cardiac death
• Sudden infant death syndrome
• Unexplained syncope
• Seizures without objective ictal activity
• Heart transplantation in the absence of coronary artery disease
• Presence of a pacemaker and/or implantable cardioverter–defibrillator in a young
person (aged <60 years)
• Muscle weakness or myopathy
• Drowning of an experienced swimmer
• Motor vehicle accident in the absence of intoxication or vehicle malfunction
• Individual who died of a supposed heart attack at a young age, in the absence of
known coronary risk factors and with no autopsy performed
of mutant mitochondria in the cell88. A definitive diag-
nosis is made only after pathology examination involv-
ing assays for mitochondrial quantity and function or by
genetic testing89. Together, mitochondrial DNA-​related
diseases constitute approximately 3% of DCMs88.
Despite the variety in presentation, the more com-
mon mitochondrial myopathy syndromes can have
characteristic cardiac features. For example, in Kearns–
Sayre syndrome, which often presents by adolescence
and is characterized by progressive ophthalmoplegia and
retinal degeneration, cardiac conduction abnormalities
(especially heart block) are present in most patients88–90.
In MELAS (mitochondrial encephalopathy, lactic aci-
dosis and stroke-​like episodes) syndrome, heart failure
can develop but is characteristically accompanied by
substantial and symmetrical left ventricular hypertro-
phy, which can present in childhood or adulthood88,90.
In MERRF (myoclonus epilepsy with ragged red fibres)
syndrome, which usually manifests during childhood,
substantial left ventricular dysfunction can occur90.
Lysosomal storage disorders. Lysosomal storage disor-
ders include diseases resulting in the accumulation of
specific cellular material, with pathogenesis involving
the heart. The presentation, manifestations and severity
of the disease processes differ greatly. The cardiac man-
ifestations of these lysosomal storage diseases have been
reviewed previously91.
Neuromuscular syndromes. The archetype of a neuro-
muscular syndrome affecting the heart is Duchenne
muscular dystrophy. Genetic variants in DMD, encoding
dystrophin, are associated with an X-​linked, recessive
pattern of inheritance. Like desmin, dystrophin con-
nects the sarcomeric proteins to the plasma membrane
via the dystroglycan complex. In Duchenne muscular
dystrophy, muscle contraction results in the loss of
cell membrane integrity and eventually cell death and
fibrofatty replacement92. Duchenne muscular dystrophy
cardiomyopathy typically manifests in the second dec-
ade of life and always involves a clear history of skeletal
myopathy92. Given that cardiac involvement is inevita-
ble if death from other causes is averted, screening for
cardiomyopathy is essential and is performed yearly in
adult patients92.
Becker muscular dystrophy can manifest with a
pattern similar to that of Duchenne muscular dystro-
phy, although cardiac involvement is not universal and,
when present, the age of onset of DCM tends to be later.
A more severe form of cardiomyopathy associated with
the DMD gene is X-​linked DCM, which does not involve
skeletal muscle and is associated with early onset (in the
second decade of life) and rapid progression93.
LMNA variants are associated with a number of
autosomal-​dominant disorders of the skeletal muscle.
In Emery–Dreifuss muscular dystrophy and limb gir-
dle muscular dystrophy type 1B, progressive wasting of
skeletal muscle occurs46, but the cardiac manifestations
(such as DCM, atrioventricular block and ventricular
arrhythmias) are similar to those in diseases associated
with LMNA variants in which a cardiac phenotype pre-
dominates94,95. Phenotypic cardiac manifestations in
Emery–Dreifuss muscular dystrophy and limb girdle
muscular dystrophy type 1B are driven by the location
of the variant within the LMNA gene96. Emery–Dreifuss
muscular dystrophy can also be associated with an
X-​linked inheritance pattern through variants in EMD,
which encodes emerin, a nuclear laminar protein.
Types of genetic testing
Candidate genetic variant testing. Testing for specific
variants in an asymptomatic individual is recommended
if a first-​degree relative has DCM that is associated with
a pathogenic or likely pathogenic gene variant; this
approach is referred to as predictive testing because the
individual does not have symptoms or known structural
disease. In the presence of specific clinical findings, such
as conduction tissue disease, advanced heart block in the
setting of DCM, or the presence of concomitant skeletal
muscle involvement in the form of an asymptomatic ele-
vation in creatine kinase level or a manifest neuromus-
cular disorder, the yield of genetic testing is high, and
targeted single-​gene testing or the use of a syndromic
cardiomyopathy gene panel can be considered97.
Cardiomyopathy gene panel testing. Various commer-
cially available gene panels are routinely used to iden-
tify a genetic variant in cardiomyopathies. The number
and types of genes offered for sequencing differ between
panels. The genes have typically been found to be asso-
ciated with cardiomyopathies in previous functional
studies or by familial segregation analysis. A study eval-
uating a large gene panel of 46 genes in 766 unselected
patients with DCM indicated that up to 37% might have
an underlying culprit variant28. In smaller gene panels
of five to ten genes, the yield of testing was <10%, but
increased to >30% with a larger panel (46 genes), albeit
with a high rate of variants of uncertain significance
(VUSs; 60%)28. Figure 2 shows an algorithm to deter-
mine whether cardiomyopathy gene panel testing should
be considered.
Whole-​exome sequencing. The clinical use of whole-​
exome sequencing is increasing as the cost associated
with this form of testing has decreased considerably
over time, and information about the presence of var-
iants in unrelated genes can be obtained. Whole-​exome
www.nature.com/nrcardio
 Reviews

sequencing can also facilitate the identification of
novel variants, particularly in genes not known to be
involved in pathogenesis, primarily by trio testing (test-
ing a proband and both parents to determine whether
the variant segregates with the disease)98. The rate of
identification of a pathogenic variant in selected, pre-
viously undiagnosed Mendelian disorders can be as
high as 25%99. However, one study evaluating the utility
of whole-​exome sequencing in HCM found that novel
variants not included in the standard gene panel were
identified in 9% of patients100.
The routine use of whole-​exome sequencing is asso-
ciated with substantial limitations101. Most importantly,
the depth of coverage is limited to the genes of interest,
so the test results must be carefully interpreted because
several issues can arise, particularly the misattribution
of a variant as being pathogenic. Second, the yield of
trio testing for the identification of novel variants can
be low if that pathogenic variant has occurred de novo
in the proband. Third, whole-​exome sequencing gener-
ally detects single-​nucleotide substitutions but can miss
larger structural genetic changes, such as copy-​number
variants, long insertions or deletions, or repetitive DNA
segments, which can result in changes in gene expres-
sion. Additionally, as indicated by the name, this type of
testing does not comprehensively sequence non-​coding
regions (intergenic areas and introns); variation in these
regions can be involved in disease pathogenesis through
the regulation of gene expression19. Given the limitations
in our knowledge of the functional importance of var-
iants in intronic or intergenic regions, whole-​genome
sequencing is not routinely used in clinical practice.
Counselling before genetic testing
Pretest counselling should be provided to all patients
with DCM, ideally by an experienced provider with
knowledge of DCM genetics, such as a genetic counsel-
lor, to facilitate patient understanding of the rationale

DCM

Known DCM-related genetic Exclude known causes of DCM

variant in family member?

High-strength recommendations Family history

• Disease-appropriate screening Yes No • Two or more family members
• Take a targeted family history with DCM?
• Genetic counselling referral • First-degree relative with sudden
• Appropriate management according cardiac death aged <50 years?
to disease process
Yes No
Familial Sporadic

Intermediate-strength recommendations Intermediate-strength recommendations

• HFSA/ESC: Consider testing the
most-affected family member
• ACC/AHA: Consider genetic testing
• Referral to an expert in cardiovascular
genetics to help to guide counselling
• HFSA: Consider testing all patients
with new-onset DCM
• ESC: Consider testing for rare or
specific cardiomyopathy, especially
if there are therapeutic implications
• ACC/AHA: Consider testing if conduction
disease present or family history of
sudden cardiac death

Genetic testing

Pathogenic or likely Variant of uncertain Benign or likely No variant

pathogenic variant significance benign variant

Genetically Monitor for variant

proven DCM reclassification over time

High-strength recommendations Idiopathic DCMa

• Institute appropriate disease-management
strategies
• Initiate cascade screening of family
• Genetic counselling referral for changes
in variant reclassification over time

Fig. 2 | genetic testing in non-​syndromic dCM. Recommended algorithm for the consideration of genetic testing in
patients with non-​syndromic dilated cardiomyopathy (DCM). HFSA , Heart Failure Society of America. aFor idiopathic DCM,
first-​degree relatives continue to be at elevated risk; consider retesting in light of the discovery of additional culprit genes.

Nature Reviews | Cardiology

Reviews
for testing, increase empowerment and improve com-
munication and dynamics within families. Given that
patients often communicate the results and implications
of genetic testing to at-​risk family members, their under-
standing of this information is imperative. Additionally,
although the cost of genetic testing is decreasing, many
patients face financial concerns especially for testing
that is considered elective and does not directly affect
medical care. Therefore, understanding the financial
implication of genetic testing for patients is important,
particularly because insurance coverage is not uniform.
However, a genetic counsellor is not trained to provide
financial advice about testing.
Patients must also understand issues relating to
the privacy of their genetic testing results and the
potential implications for insurability for themselves
and their family members. The Genetic Information
Nondiscrimination Act (GINA) is a federal law in the
USA that prohibits the use of genetic information for
discrimination by employers and health insurers.
However, this law has limitations because it does not
apply to life, long-​term care or disability insurance.
Exceptions also exist for some employers and forms of
health insurance (such as for government employees and
active members of the military). Patients and families
might have difficulty obtaining life and health insurance,
even when seeking care for a pre-​existing condition102.
Because private insurance has a smaller role in Europe,
few countries have formally regulated the use of genetic
testing for risk assessment, but several European coun-
tries provide protection against the use of genetic testing
information for determining life insurance premiums or
eligibility. Most countries in Asia do not have similar
regulatory protection103.
Pretest counselling provides a patient with the best
opportunity to evaluate a wide range of genetic testing
options, which hinges on risk assessment. As described
above, genetic testing can range from site-​specific or
gene-​specific testing to large disease-​specific panels to
whole-​exome sequencing. The implications and possible
results of these tests differ widely, and setting appropriate
expectations for patients before they undergo a genetic
test is important, especially with whole-​exome sequenc-
ing, which can result in secondary genetic findings that
have other health implications. Additionally, many syn-
dromic causes of DCM exist, so obtaining a syndromic
gene panel is imperative if a patient is suspected of hav-
ing a syndromic form of DCM. Fortunately, comprehen-
sive cardiomyopathy gene panels usually include genes
that have been implicated in syndromic causes of DCM.
Interpreting genetic test reports
ACMG guidelines. The ACMG published a set of
guidelines in 2015 for the standardized interpretation
of genetic variants. These guidelines have helped to
provide consistent terminology between laboratories
and clinicians in the classification of variants as being
pathogenic, likely pathogenic, a VUS, likely benign or
benign20. However, despite the objectivity of the criteria,
differences in interpretation persist between laborato-
ries and clinicians, with one study indicating that the
laboratory classifications of 18% of 688 variants differed
by more than two levels from the classification obtained
by an evidence-​based algorithm applied by a group of
clinicians104. Similar rates of interlaboratory variability
have been observed in other studies105,106. As a result of
this heterogeneity in interpretation, an attempt to cen-
tralize variant classification has been initiated, initially
using MYH7 as a prototype because of the prevalence of
pathogenic variants in this gene107.
VUS: determining significance. Often, genetic testing is
inconclusive owing to the absence of a variant or the pres-
ence of a benign variant or one or more VUSs. Adherence
to the criteria outlined by the ACMG for determining
the pathogenesis of a variant is important20,107. In some
scenarios, the genetic significance of a VUS can be deter-
mined by performing a segregation analysis in family
members. Many genetic laboratories offer free testing
of family members if a VUS is found that meets certain
criteria. However, this approach should be interpreted
cautiously because segregation analysis does not always
determine causality, and penetrance can vary108. In vitro
functional characterization of a VUS in induced pluri-
potent stem cell-​derived cardiomyocytes has also been
useful in determining its pathogenicity109.
Cascade screening. The identification of a pathogenic or
likely pathogenic variant in a DCM-​susceptibility gene
is an indication for family cascade screening. Testing
of asymptomatic family members guides the necessity
for echocardiographic screening and is a cost-​effective
approach. If an at-​risk family member tests negative for
a previously identified pathogenic or likely pathogenic
variant in the context of a negative baseline cardiac
evaluation, ongoing cardiac evaluation is not usually
warranted, depending on the strength of the association
between the variant and the disease25. Family members
who test positive for a previously identified pathogenic
or likely pathogenic variant should receive tailored
cardiac screening and preventative measures. Cascade
screening in first-​degree relatives can also help to deter-
mine the need to perform genetic screening and cardiac
evaluations in distant relatives.
Genetic risk factors and prognosis
Markers of genetic susceptibility. Genome-​wide asso-
ciation studies (GWAS) have sought to discover novel
genetic markers to predict the development of DCM;
however, these markers have not been implemented in
clinical practice. The single-​nucleotide polymorphisms
(SNPs) identified in these studies suggest that common
genetic variation can confer increased risk at a popu-
lation level110–113. However, associations are challenging
because attribution of causality can be particularly diffi-
cult in intronic regions, and mechanisms must be sought
for variation in novel loci114,115.
The use of GWAS has also yielded potential insights
into differential risk and disparate outcomes according
to ethnicity116. Unique genetic risk markers in African
American individuals have been discovered that are
associated not only with left ventricular remodelling
but also with incident heart failure events, and these
risk markers are not present in similar European
www.nature.com/nrcardio

cohorts117,118. Studies that implicate common genetic var-
iation as risk loci need to be replicated in large, diverse
and well-​characterized populations and functionally val-
idated before being used in the clinic in the form of risk
scores for disease prediction.
Use of genetics in prognosis. In addition to predicting the
risk of developing DCM, considerable interest exists in
using genetic markers to determine prognosis in DCM
and to help with risk stratification. For example, patients
with pathogenic LMNA variants might be at increased
risk of ventricular arrhythmias, irrespective of the degree
to which LVEF is reduced, meriting the implantation of
a cardioverter–defibrillator for the primary prevention
of sudden cardiac death119,120. SNPs can also be inform-
ative for risk stratification. For example, in a large-​scale
GWAS, one SNP on chromosome band 5q22 was asso-
ciated with a 36% increased risk of death in patients with
heart failure121. Other GWAS have identified an associa-
tion between SNPs and an increased risk of heart failure
and cardiovascular events122,123. However, the routine
use of genetic testing for prognostication in arrhythmic
DCM requires further data44.
Heart failure medical therapy and pharmacogenetics.
Given the ubiquitous use of neurohormonal blockade
therapy in heart failure, with excellent data to support its
use for cardiac reverse remodelling, functional improve-
ment and increased survival, substantial interest lies in
identifying which patients will benefit more or less from
these therapies. Research has provided some insight
into the relative efficacy of neurohormonal blockade in
patients with heart failure stratified by genetic variants,
contributing to the application of pharmacogenetics.
Some differences in individual response to β-​blockade
are likely to be caused by genetic polymorphisms within
the population in the gene encoding the β-​adrenergic
receptor. Indeed, polymorphisms in ADRB1 and in GRK5,
encoding the downstream G-​protein-coupled recep-
tor kinase 5, influence responsiveness to β-​blockade21.
Other data have shown that amino acid substitutions
in the β-​adrenergic receptor, such as Arg389Gly, might
affect responsiveness to β-​blockade, possibly mediated
through decreased activation of the renin–angiotensin–
aldosterone system124–126. However, this polymorphism
has not been associated with a change in morbidity or
mortality in substudies of the WOSCOPS trial127 or the
MERIT-​HF trial128.
Similarly, genes encoding angiotensin II and its asso-
ciated receptors, which are involved in the pathogenesis
of heart failure and are a target of antagonism in rou-
tine guideline-​directed medical therapy, are associated
with polymorphisms that confer a differential response
to therapy. Data suggest that having a homozygous DD
genotype for the ACE gene, which raises angiotensin II
levels, combined with a polymorphism in AGTR1
(encoding the type 1 angiotensin II receptor) might con-
fer higher levels of activation of the renin–angiotensin–
aldosterone system and worse prognosis, despite treat-
ment with angiotensin-​c onverting enzyme (ACE)
inhibitors129,130. In a prospective, observational study of
patients with congestive heart failure, the presence of at
Nature Reviews | Cardiology
Reviews
least one D allele of the ACE gene was associated with
lower survival, especially if the patients were not receiv-
ing β-​blocker therapy131. However, in another trial in
which patients were stratified according to the presence
of previously identified pathogenic variants in AGTR1,
no differences in long-​term mortality were identified132.
Although not associated with a large effect size, multiple
SNPs have been identified that increase the risk of ACE
inhibitor-​induced angio-​oedema133. Routine testing for
SNPs associated with differential responses to neuro-
hormonal blockade is not routinely performed in the
clinical setting owing to a lack of clinical validation and
utility, but continued research to individualize medical
therapy holds promise to improve outcomes134.
Gene–environment interaction. The interaction between
environmental factors and the underlying genetic make-​
up of an individual is critically important. Analogous
to a multiple-​hit hypothesis in cancer, environmental
factors and triggers might affect the phenotypic expres-
sion of DCM in a patient with an underlying genetic
predisposition135. For example, peripartum cardiomy­
opathy has been associated not only with a familial pre-
disposition but might be caused by the combination of
an underlying pathogenic variant and the physiological
stress of pregnancy136,137. Similarly, genetic predisposi-
tion might affect the cardiotoxicity of anthracyclines and
other antineoplastic agents138. Indeed, when carefully
evaluated, environmental triggers might be associated
with a generally worse prognosis if an underlying genetic
predisposition to the disease exists139.
Uncertainties and future directions
Several barriers exist to the use of genetics in the care of
patients with DCM. The foremost problem limiting our
identification of culprit genes is the frequency of VUSs,
which require functional studies or segregation analy-
ses for interpretation28. Some genetic variants might be
necessary but not sufficient for the phenotypic manifes-
tation of DCM and might require other so far unidenti-
fied genetic or environmental factors to manifest overt
disease135. Additionally, as described above, most of the
isolated culprit genes that have been identified are auto-
somal dominant or X-​linked, but many more genetic
variants might be inherited in an autosomal-​recessive
pattern, which can be more difficult to identify in familial
DCM and so are potentially under-​recognized23.
Broad interest exists in understanding the possible
role of epigenomics and other ‘omics’ in chronic dis-
ease and has only lately been evaluated in the context
of cardiomyopathy. Changes in DNA methylation have
been shown to alter the expression of genes involved
in energy metabolism, with an effect on cardiomyo-
cyte function140. An integrated omics approach might
improve our understanding of disease pathogenesis, and
the ‘omic’ patterns developed using artificial intelligence
in large populations could potentially be used for precision
diagnosis, prognosis and treatment of heart failure.
The limited access to genetic counsellors and geneti-
cists has restricted the use of genetics in the routine care
of patients with DCM. One method to improve access is
to use videoconferencing for interviews (telemedicine),
Reviews

in this context termed ‘telegenetics’, which is supported
by most genetic counsellors141,142. However, new and
innovative methods to educate and inform patients and
physicians need to be developed to improve access to
genetic testing that could complement genetic counsel-
ling by licensed providers. Additionally, on a practical
level, poor patient literacy and ineffective education or
communication between physicians and patients about
the results and implications of genetic testing can hinder
the evaluation or create challenges for interpretation.
Conclusions
Substantial progress has been made in the field of car-
diovascular genetics and in our understanding of the
genetic basis of DCM. Increasing numbers of culprit rare
genetic variants have been validated, and new common
genetic markers for the risk of DCM have been identi-
fied. The routine use of expanded gene panels in DCM
increases the diagnostic yield, albeit with an increased
risk of identifying VUSs. High-​throughput, in vitro
cellular functional validation and segregation analysis
have helped to interpret VUSs. Implementation of rou-
tine genetic testing for DCM in heart failure clinics is a
challenge, with limited availability of genetic counsellors.
The heart failure community needs to make progress in
the identification and validation of genetic markers of
DCM risk, disease progression and response to therapy,
which will eventually fulfil the promise of precision
medicine in heart failure, with the hope of improved
outcomes for patients and their families.
Published online xx xx xxxx

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Author contributions
All the authors researched data for the article, wrote the man-
uscript and reviewed and edited it before submission. A.N.R.
and N.L.P. contributed to discussions about the article
content.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Cardiology thanks L. Mestroni, A. Morales,
G. Sinagra and M. van den Berg for their contribution to the
peer review of this work.
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