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Familial Dilated Cardiomyopathy
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Familial Dilated Cardiomyopathy Stacey Peters , MBBS a,b,c, Renee Johnson , PhD, MGC d, Samuel Birch , MBBS e, Dominica Zentner , PhD a,b,c, Ray E. Hershberger , MD f,g, Diane Fatkin , MD d,e,h,* a
Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, Australia Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, Vic, Australia c Department of Medicine, University of Melbourne, Melbourne, Vic, Australia d Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia e Cardiology Department, St. Vincent’s Hospital, Sydney, NSW, Australia f Divisions of Human Genetics and Cardiovascular Medicine, Wexner Medical Center, Columbus, OH, USA g Dorothy M Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA h St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia b
Received 3 October 2019; accepted 18 November 2019; online published-ahead-of-print xxx
Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only w25–40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotypephenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotypebased therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management. Key words
Familial dilated cardiomyopathy Genetics
Introduction Dilated cardiomyopathy (DCM) is a common heart muscle disease that is estimated to affect up to 1 in 250 individuals [1]. It can occur as a primary abnormality of myocardial function or in association with a myriad of cardiac and extracardiac disorders [1]. DCM is often manifested as an inherited trait in families [2], and substantial progress has been made in elucidating genetic causes of DCM using
family-based analyses. DCM is the most genetically and phenotypically heterogeneous of the inherited cardiomyopathies and this complexity has made it difficult to study from a genetic perspective [3]. In recent years, new perspectives have emerged and the boundary of what is considered to be “genetic” DCM is no longer limited to familial disease. In particular, pathogenic gene variants are thought to underlie many sporadic cases of idiopathic DCM [4] and have also been found in patients with acquired causes of DCM,
*Corresponding author at: Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst NSW 2010, Australia. Tel.: 161 2 9295 8618; Fax: 161 2 9295 877., Email: [email protected]; Twitter: @FatkinLab Ó 2019 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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including alcoholic cardiomyopathy and chemotherapyrelated cardiac toxicity [5–7]. These observations suggest that an individual’s genetic makeup is a key determinant of DCM susceptibility that needs to be considered, irrespective of family history or other identifiable risk factors. Families in which DCM is clearly inherited as a Mendelian trait remain a powerful resource for studying the genetics of this condition. Advances in sequencing technologies are now providing new platforms for genetic testing and unprecedented opportunities for elucidating the genetic architecture of DCM. Although more families are being tested around the world, interpreting the results has not been straightforward. More than 100 genes have been associated with DCM [8], and most of these have also been shown to have extensive variation in the normal population [9,10]. Distinguishing pathogenic from benign variants in such a large number of genes remains a major challenge. Despite this, a growing subgroup of genes are being identified that have distinct genotypephenotype patterns and corresponding clinical imperatives [11]. Ongoing research is urgently required to establish clinical guidelines for affected and unaffected pathogenic gene variant carriers, as well as those where no pathogenic variant is found. In this review, we will discuss topical issues in DCM, addressing questions that are relevant to the general cardiologist including: (i) who should be suspected of a possible genetic cause of DCM and what further workup may be useful, (ii) how to interpret a genetic test result and what new genes to be aware of, and (iii) how to approach management both when a gene variant is found and when it is not found, including the frequency of monitoring, best imaging modalities and lifestyle recommendations.
Clinical Presentation and Investigation Traditionally, a diagnosis of familial DCM is made when two or more first-degree relatives have “idiopathic” DCM and/or unexplained death at a young (,35 years) age [12]. However, caution is needed when assessing a patient with apparent sporadic DCM, since this may be the first presentation of disease in a kindred or represent a negative DCM family history as a consequence of small family size or variable penetrance. In this regard, a number of other features may provide clues that there could be an underlying genetic aetiology (Table 1). A detailed clinical history and examination should take place in all newly-diagnosed idiopathic DCM patients, especially young-onset cases. A comprehensive three-generation family history is necessary, particularly assessing for sudden cardiac death or heart failure. Ideally, autopsy reports or death certificates should be tracked down to corroborate information. The first and simplest investigation is an electrocardiogram (ECG). Conduction disease should be considered, including the presence of PR or QRS prolongation and atrial or ventricular ectopy. However, the most important
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Table 1 Clinical features that increase suspicion of underlying genetic disease in an index patient with DCM. Family history of DCM Family history of other cardiac features e.g. left ven-
tricular hypertrophy, valvular abnormalities, congenital heart defects, arrhythmias Family history of sudden cardiac death or cardiac arrest Young onset (,35 years) of idiopathic DCM Young onset with an acquired causal factor insufficient to explain DCM Extensive myocardial fibrosis on CMR, biopsy or autopsy in a young patient Concomitant conduction disease on ECG Concomitant early or prominent atrial arrhythmias Concomitant early or prominent ventricular arrhythmias or aborted cardiac arrest Extra-cardiac manifestations e.g. skeletal myopathy, neurological defects, lipodystrophy, dysmorphism, intellectual disability
Abbreviations: DCM, dilated cardiomyopathy; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram.
diagnostic test is a thorough echocardiogram. Dilated cardiomyopathy due to genetic or acquired causes may be indistinguishable but certain additional features may be present in the genetic forms, including increased left ventricular wall thickness, prominent left ventricular trabeculations and right ventricular or atrial chamber enlargement or dysfunction. These features are important because some DCM genes have been reported to cause other cardiac phenotypes, which can occasionally overlap in individuals and within families. Table 2 lists some of the cardiac and extra-cardiac phenotypic manifestations that have been reported in association with DCM genes. All first-degree relatives should be screened with history, exam, ECG and echocardiogram. It is worth considering that relatives may have more subtle features on ECG or echocardiography that, while not indicating a diagnosis of DCM, may still be relevant. These features include left bundle branch block, left ventricular enlargement, other chamber enlargement, isolated mildly reduced systolic function (left ventricular ejection fraction 50–55%), reduced global longitudinal strain, segmental wall motion abnormalities or hyper-trabeculation [13]. Other tests can be performed when further information is required. These include: (i) a treadmill stress echocardiogram to assess for expected augmentation of left ventricular systolic contraction during exercise, (ii) ambulatory ECG monitoring to evaluate for frequent atrial or ventricular extrasystoles, especially when there is a prominent family history of arrhythmias, cardiac arrest or sudden death, or (iii) cardiac magnetic resonance imaging (CMR), which can be useful to
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Table 2 Additional cardiac and non-cardiac phenotypic features observed with genetic variants associated with adultand paediatric-onset DCM*. Cardiac phenotypes Ventricular arrhythmias
ABCC9, ACTN2, CHKB, DES, DMPK, DSC2, DSG2, DSP, FLNC, KCNJ12, KCNJ2, KCNQ1, LMNA, MyBPHL, NKX2.5, PLN, RBM20, RYR2, SCN5A, TMEM43, TTN, ZNF9
Atrial arrhythmias/atrial fibrillation Sudden cardiac death
ABCC9, ACTN2, DMPK, EMD, FLNC, GATA4, GATA5, GATA6, KCNQ1, LMNA, LRRC10, MURC, MyBPHL, NKX2.5, RBM20, RYR2, SCN5A, TBX5, TNNI3K, ZNF9 ABCC9, ACTN2, AKAP9, CAV-3, CHKB, DES, DMPK, DSP, EMD, FLNC, KCNJ2, KCNQ1, LMNA, NKX2.5, PLN, RBM20, RYR2, SCN5A, ZNF9
Conduction disease
ACTA1, ACTN2, CAV-3, CHKB, DES, DMPK, DSP, EMD, LDB3, LMNA, MT-ND5, MURC, MyBP-HL,
Hypertrophic
ABCC9, ACAD9, ACTA1, ACTC1, ACTN2, ALPK3, ANKRD1, BAG3, CAV-3, CRYAB, CSRP3, DES, FHL2,
MYH6, MYH7, NKX2.5, SCN5A, TBX5, TNNI3K, TRPM4, ZNF9 cardiomyopathy
FHOD3, FLNC, LAMP2, MTATP6, MT-CYB, MT-ND1, MT-ND2, MT-ND5, MT-RNR2, MT-TI, MT-TK, MTTL1, MYBPC3, MyBP-HL, MYH6, MYH7, MYL2, MYL3, MYOM1, MYPN, NEXN, OBSCN, PLN, PSEN2, RAF1, TAZ, TCAP, TMEM70, TNNC1, TNNI3, TNNT2, TPM1, TTN, VCL
Left ventricular
ACTC1, ACTN2, DNAJC19, DSP, KCNQ1, LDB3, LMNA, MYBPC3, MYH7, PLEKHM2, PRDM16, RYR2,
noncompaction
TAZ, TNNT2, TPM1, TTN
Arrhythmogenic
DES, DSC2, DSG2, DSP, EYA4, LDB3, LMNA, OBSCN, PKP2, PLN, PSEN1, RBM20, RYR2, SCN5A,
cardiomyopathy
TMEM43, TTN
Restrictive cardiomyopathy
ACTC1, BAG3, CRYAB, DES, FLNC, MT-RNR1, MYBPC3, MYH7, MYL2, MYL3, MYPN, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR (amyloid)
Congenital heart disease
ACTC1, ANKRD1, CASZ1, GATA4, GATA5, GATA6, HAND1, MYBPC3, MYH6, MYH7, NEXN, NKX2.5, RAF1, TAZ, TBX20, TBX5
Brugada syndrome/early
ABCC9, AKAP9, DSG2, DSP, KCNJ2, MYH7, PKP2, RYR2, SCN5A, TRPM4
repolarization Long QT syndrome
AKAP9 (LQT11), BAG3, CAV-3 (LQT9), DNAJC19, KCNJ2 (LQT7), KCNQ1 (LQT1), RYR2, SCN5A (LQT3), TRPM4
Short QT syndrome
KCNJ2, KCNQ1
Catecholaminergic
KCNJ2, RYR2
polymorphic VT Idiopathic VT/VF
RYR2, SCN5A
Myocarditis
DSP
Pre-excitation
LAMP2, MT-ND5, MYH6
Coronary vasospasm
ABCC9
Endocardial fibroelastosis
NEBL
Non-cardiac phenotypes Congenital syndromes
ABCC9 (Cantu), ALMS1 (Alstrom), CHKB, EEF1A2, RAF1 (Noonan), TAX1BP3, TAZ (Barth), TBX5 (Holt-
Mitochondrial syndromes
Oram), UBR1 (Johansson-Blizzard) ACAD9 (Leigh syndrome), DNAJC19, MTATP6, MT-CO2, MT-CO2, MT-CYB, MT-ND1, MT-ND2, MT-ND5, MT-RNR2, MT-TE, MT-TI, MT-TK, MT-TL1, MT-T, MTTS1, RMND1, TMEM70
Congenital disorders of
ALG6, DOLK, PGM1
glycosylation Myopathy
ACTA1, ANO5, BAG3, CAV-3, CHKB, CRYAB, DES, DMD, DMPK (myotonic dystrophy 1), EMD, FKRP, FLNC, KCNJ2, LAMA2, LDB3, LIMS2, LMNA, MYH7, MYL2, MYPN, PNPLA2, POMT1, POMT2, SGCA, SGCB, SGCD, SGBG, SYNE1, TCAP, TOR1AIP1, TTN, ZNF9 (myotonic dystrophy 2)
Neuropathy Developmental impairment
BAG3 CHKB, POMT1, POMT2
Congenital cataracts
CRYAB
Cutaneous features
DSP, LMNA, PPP1R13L
Hearing impairment
EYA4, KCNQ1, MT-RNR1
Juvenile diabetes
GATA4, GATA6
Dysmorphism
KCNJ2, RRAGC
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444 445 446 Cardiac phenotypes 447 448 Lipodystrophy LMNA 449 Familial dementia PSEN1, PSEN2 450 Metabolic or storage disorders LAMP2 (Danon disease), OGT (atypical mucolipoidosis), SLC22A5 (carnitine deficiency), TTR (amyloidosis), 451 TXNRD2 (glucocorticoid deficiency) 452 453 454 Abbreviations: DCM, dilated cardiomyopathy; VT, ventricular tachycardia; VF, ventricular fibrillation. 455 *Bolded genes denote those for which there is robust evidence for DCM causation. 456 457 458 young-onset (,35 years) or associated with high-risk feaclarify functional information and exclude alternative causes 459 460 tures (Table 1, Figure 2) [25]. for DCM such as sarcoidosis, ischaemic cardiomyopathy or 461 A number of different methods for genetic testing can be infiltrative disease. CMR is also increasingly used to identify 462 used. Panel sequencing (PS), which focusses on testing a patterns of fibrosis or fat infiltration that can indicate an 463 selection of varying numbers of disease-associated genes, arrhythmogenic form of familial cardiomyopathy [14]. In the 464 remains the most widely used technique in most clinical absence of these, DCM due to any cause often results in de465 laboratories. A disadvantage of PS is that panel composition grees of mid-wall fibrosis, which can be prognostic in sudden 466 is not uniform across laboratories. Moreover, as advances in death prediction [15]. It is expected that CMR will prove 467 468 research implicate new genes, there is an ongoing need for useful in detecting early DCM in variant carriers (Figure 1), 469 panels to be redesigned. As a consequence, patient testing though most early disease features including feature470 may need to be repeated using updated panels or alternatracking-derived global longitudinal strain, T1 mapping and 471 tive methods. There has been a move in some centres to extra-cellular volume are yet to be formally studied in this 472 offer whole-exome sequencing (WES), which provides insetting. 473 formation about all genes. There are a number of pitfalls of 474 WES however, including inconsistent sequence coverage 475 476 and gaps, and studies have not consistently shown an 477 improved yield of mutation detection in adult cohorts 478 Advances in human genome sequencing technology have [26,27]. WES also does not provide information about non479 dramatically increased the scope for genetic testing in DCM. coding regions which are increasingly being suspected to 480 Until recently, genetic testing in DCM was thought to have contribute to heritable human diseases [28,29]. Whole481 limited value compared to other inherited cardiomyopathies genome sequencing (WGS) has the advantage of assessing 482 due to a low yield and modest treatment implications, and all coding and non-coding regions, as well as detecting large 483 testing was only recommended for specific genes, such as copy number variation. Emerging studies support the po- Q2 484 485 LMNA and SCN5A, that have a characteristic phenotype tential use of WGS as a first-line genetic testing method 486 (DCM and conduction-system abnormalities) and significant [27,30], although at this stage it remains mostly in the 487 complications [16]. However, high-throughput next-generaresearch domain. 488 tion sequencing has enabled the discovery of additional Regardless of the test employed, variant curation is 489 important genes, such as such as TTN, in which truncating currently the major challenge in DCM. Many family variants 490 variants are identified in w15–20% of DCM families [17], are unique and lack supporting evidence to show that they 491 and genes such as RBM20 and FLNC that can be highly 492 have function-altering effects. Further, family segregation 493 arrhythmogenic [18–20]. As the clinical utility of genetic analysis may be underpowered in small kindreds, and 494 information is increasingly recognised, a number of propenetrance and expressivity are often highly variable. The 495 fessional societies have updated practice guidelines for ACMG has devised a set of guidelines for ranking the po496 which patients need genetic testing [12,21–24]. In reality, tential pathogenicity of variants and this classification 497 testing practices differ with geographic location, access to method has become widely used in clinical practice [31]. 498 services, and reimbursement. The Heart Failure Society of Variants are classified into one of five grades: pathogenic, 499 America/American College of Medical Genetics and Ge500 likely-pathogenic, unknown pathogenicity, likely benign and 501 nomics (ACMG) guidelines recommend genetic testing in benign. Only the top two grades, “pathogenic”, and “likely502 all patients with idiopathic DCM, regardless of family pathogenic” are considered to be clinically significant and 503 history [22,23] and in the United States this is common can be used for patient management decisions and for pre504 practice. Currently, in Australia, most cardiac genetics dictive testing in relatives. The ACMG criteria take into 505 clinics will offer testing to patients with a clear pattern of account a number of factors, including whether or not a 506 familial DCM. Genetic testing is also offered by some servariant has been previously seen in affected cases and/or the 507 vices for selected patients with idiopathic DCM that is 508 general population, evidence of family segregation, and
Table 2 (continued).
Genetic Testing
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Familial Dilated Cardiomyopathy
Figure 1 Cardiac magnetic resonance imaging of genotype-positive patient with early phenotypic changes. (A) Volumetric analysis of a mid-ventricular short-axis slice in end-diastole. Endocardial, epicardial and papillary muscle contours shown. (B) Feature-tracking-derived global longitudinal strain measurement of a four-chamber cine series. (C) Late gadolinium enhanced image demonstrating the absence of the classic mid-wall enhancement often seen in established dilated cardiomyopathy (see F). (D) Native T1 mapping image of a mid-ventricular short-axis slice demonstrating interstitial expansion in the inferoseptum (black arrow). (E) Steady-state free precession-based mid-ventricular short-axis cine image in end-diastole in a normal heart. (F) Late gadolinium enhanced image in a patient with dilated cardiomyopathy.
evidence that the variant has a disease-relevant functional effect [31]. For many variants, there is insufficient information to meet the stringent criteria for pathogenicity or likely-pathogenicity, and some deleterious variants may be missed. All variants warrant periodic re-assessment as new laboratory or family evidence emerges to favour, or downgrade, initial pathogenicity classifications. This is particularly the case for “variants of unknown significance”. One strategy to reduce the level of uncertainty is to limit the list of evaluated DCM genes to a core group of disease-causing genes and to disregard variants in genes for which there is weak evidence for roles in DCM
pathogenesis. Horvat et al. [10] used a gene-centric approach to critically assess a set of 41 DCM genes represented on two gene sequencing panels and found that only 14 genes had robust evidence for disease association. Genes that are currently considered high-confidence DCM disease genes, including the “group A” genes from Horvat el al.’s study are indicated in Table 2. Due to the challenges in variant interpretation, genetic testing is ideally performed in a multidisciplinary clinic. Input from molecular cardiologists, clinical geneticists, laboratory geneticists, and genetics counsellors is usually required to analyse genetic test results and devise a plan for clinical management.
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Impact of Genetic Test Results on Family Management Scenario 1: No Pathogenic Variant is Found Despite improvements in genetic testing, 60–75% of families with clearly autosomal dominant familial DCM do not currently receive a clear genetic explanation for their condition [22,23]. Various hypotheses exist as an explanation for this including: (i) the disease-causing gene or gene variant was not detected with the technology utilised, (ii) the variant was detected but its pathogenicity was underappreciated or failed to meet the stringent criteria for pathogenicity outlined in ACMG clinical guidelines [31], or (iii) there are multiple minor variants and/or non-genetic factors contributing to disease in the family. These families should not be considered at lower risk of DCM if a single pathogenic variant is unable to be found and periodic reassessment is indicated (Figure 2). Variant interpretation is a dynamic process and may change over time with expansion of the knowledge base. Further, if additional family members are diagnosed with DCM, repeated family segregation analysis may change the interpretation of borderline variants. For clinical management, those with symptomatic DCM are treated according to standard guidelines for nonischaemic cardiomyopathy, though certain specific features may need to be considered (Figure 2). For example, if there is a strong family history of sudden cardiac death or arrhythmias, periodic rhythm monitoring is often required and earlier than usual consideration of a primary prevention implantable cardioverter-defibrillator (ICD) is warranted if high risk features are evident. If the phenotype is severe with rapid deterioration to a decompensated phase of disease, an earlier than usual referral to a heart transplant service is reasonable. For those without DCM, periodic monitoring should continue until late in life. Unfortunately, without a means to identify members at risk, all first-degree relatives need to remain in screening with ECG and echocardiography approximately every 2 years. In certain circumstances a one-off or periodic less frequent CMR could be considered.
Scenario 2: Pathogenic Variant is Present Variant-negative relatives Depending on the level of certainty that an identified variant is the primary driver of disease, genotype-negative family members may be cautiously released from screening (Figure 2). However, where there is uncertainty about the true pathogenicity of a variant, either from the laboratory or clinical side, it is our view that ongoing family monitoring may be required (Figure 2). Periodic surveillance may also be prudent for members of families with truncating TTN variants, since additional genetic or acquired factors may be present that can independently contribute to DCM risk [5–7,32]. Variant-positive, affected index patients and relatives With some exceptions (see below), familial DCM has generally been managed in line with other forms of DCM with the only additional consideration being family screening. Now, there is a growing literature on specific genotype-phenotype correlations that allows a personalised approach to be taken in some circumstances. Primarily, this refers to monitoring for unique features and timing of ICD implantation and heart transplantation. Certain DCM genes, such as LMNA and SCN5A, can cause malignant arrhythmias despite a relatively preserved ventricular ejection fraction, and routine guidelines for primary prevention ICDs may not be appropriate in these patients [11]. Patients with LMNA variants may also need early consideration of heart transplantation as they frequently have a rapidly progressive clinical course [33]. Currently, there are few instances where personalised pharmacotherapy is appropriate. An important exception is the p.R222Q SCN5A variant that has been associated with DCM and complex ventricular and atrial arrhythmias in a number of kindreds. Functional studies have shown that this variant has a gain-of-function effect on cardiac sodium channel activity, and drugs with sodium channel-blocking properties have proven to be highly effective [34–36]. For the majority of families, however, genespecific management strategies remain largely in the realm of research. Physicians managing these patients should be mindful of changes in the literature that may indicate nuanced management.
Figure 2 Flow chart for genetic testing and clinical management of an index case in whom a genetic cause of DCM is suspected. Genetic testing is recommended for patients with a family history of DCM and may also be undertaken for patients diagnosed with idiopathic DCM at a young age or with specific associated features (see Table 1). Management guidelines will vary depending on the presence or absence of a causative genetic variant and whether or not an individual has DCM. At each review, management decisions should take into account any new clinical and/or genetic information. *High risk arrhythmic features include: history of syncope, family history of sudden cardiac death, ECG with conduction block, late gadolinium enhancement on CMR, 24-hour ambulatory ECG with .1,000 premature ventricular complexes or non-sustained ventricular tachycardia, variants in highly arrhythmic genes eg. LMNA, SCN5A, FLNC, RBM20. # Features suggesting disease severity include: rapid clinical deterioration, family history of heart failure, heart transplantation or early deaths. Abbreviations: DCM, dilated cardiomyopathy; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram.
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Variant-positive, unaffected relatives Periodic monitoring is recommended for unaffected carriers of known pathogenic variants, and the type and aggressiveness of monitoring may be tailored to the specific gene or family history in some circumstances [14] (Figure 2). Carriers of variants that cause arrhythmic types of cardiomyopathy should be periodically reviewed for arrhythmic symptoms and ambulatory ECG monitoring may be included in the assessment. Some genes are associated with a more aggressive course and these may warrant more frequent follow-up. However, for most disease genes, limited data exists on the expected course, and without a clear guide of how frequently to monitor these patients we adhere to the recent American Heart Association scientific statement recommendation with an ECG and echocardiogram every 1–3 years [21]. Physicians should bear in mind that age-related penetrance is seen for many DCM gene variants so periodic monitoring should continue into later life [22]. At this stage, there are no evidence-based data for the optimal timing and indications for prophylactic pharmacotherapy in variant carriers and further research is critically needed. Acquired, Environmental, and Lifestyle Factors In all patients with DCM, regardless of whether or not a causative genetic variant has been found, there are a number of additional factors that should be considered in management, including prompt treatment of reversible arrhythmias and attention to co-morbidities, such as hypertension, coronary artery disease, diabetes, and obesity. There is increasing interest in gene-environment interactions and identification of lifestyle factors that might exacerbate myocardial dysfunction in variant carriers. Recent studies have highlighted subsets of patients with alcoholic cardiomyopathy and chemotherapy-related cardiac toxicity who carry deleterious variants in cardiomyopathy genes such as TTN [5–7]. Whether both genetic and acquired factors (“two hits”) are required for DCM manifestation, or the acquired factors acted to accelerated disease onset in genetically-predisposed individuals is unclear. In any case, identification of variant carriers in these settings may impact on patient management and has implications for clinical and genetic screening of other family members. Overall, evidence for lifestyle factor associations in genetic DCM are currently scarce, and more research is required before clear recommendations can be made. In genotype-positive females in DCM families, pregnancy should be actively recognised as a time of cardiomyopathic risk. These women should undergo pre-pregnancy counselling and serial cardiac assessment, even if baseline cardiac function is normal [37,38]. Interestingly, in cohorts of patients with peripartum cardiomyopathy, w20% cases have been found to carry deleterious cardiomyopathy gene variants [39,40], raising suspicion that much of peripartum cardiomyopathy is in fact genetically-mediated DCM.
S. Peters et al.
964 965 966 The genetics of DCM is a rapidly moving field and emerging 967 evidence is set to change the way we view and manage 968 affected patients and their families. It is important for the 969 general cardiologist to appreciate which patients should be 970 suspected as having genetically-mediated disease, what 971 further workup is required, and who should be referred for 972 973 genetic assessment. Genetic testing is evolving and, while 974 complexities in variant assessment remain, new genotype975 phenotype associations are pointing to personalised man976 agement strategies for a growing subgroup of families. 977 Nonetheless heterogeneity in genetics and phenotypic fea978 tures means ongoing uncertainty for many families, and 979 specialist cardiac genetics clinics are needed to interpret ge980 981 netic results and determine a course of action, with active 982 recognition that this will likely require future modification as 983 time and technology progress. 984 985 986 987 988 None. 989 990 991 992 993 We thank Associate Professor Andrew Jabbour from the 994 Advanced Cardiac Imaging Centre at St Vincent’s Hospital 995 Sydney, for helpful discussions. Dr Peters is supported by an 996 Australian Postgraduate Award from the University of 997 Melbourne. Dr Fatkin is supported by the National Health 998 999 and Medical Research Council of Australia, Victor Chang 1000 Cardiac Research Institute, Estate of the Late RT Hall, and 1001 Q3 the Simon Lee Foundation. 1002 1003 1004 1005 [1] Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: 1006 the complexity of a diverse genetic architecture. Nat Rev Cardiol 1007 2013;10:531–47. 1008 [2] Petretta M, Pirozzi F, Sasso L, Paglia A, Bonaduce D. Review and meta1009 analysis of the frequency of familial dilated cardiomyopathy. Am J Car1010 diol 2011;108:1171–6. 1011 [3] Bondue A, Arbustini E, Bianco A, Ciccarelli M, Dawson D, De Rosa M, et al. Complex roads from genotype to phenotype in dilated cardiomy1012 opathy: scientific update from the Working Group of Myocardial 1013 Function of the European Society of Cardiology. Cardiovasc Res 1014 2018;114:1287–303. 1015 [4] Kinnamon DD, Morales A, Bowen DJ, Burke W, Hershberger RE, DCM 1016 Consortium. Towards genetics-driven early intervention in dilated car1017 diomyopathy: design and implementation of the DCM Precision Medicine Study. Circ Cardiovasc Genet 2017;10:e001826. 1018 [5] Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar1019 Mendiguchia J, et al. Genetic etiology for alcohol-induced cardiac toxicity. 1020 J Am Coll Cardiol 2018;71:2293–302. 1021 [6] Linschoten M, Teske AJ, Baas AF, Vink A, Dooijes D, Baars H, et al. 1022 Truncating titin (TTN) variants in chemotherapy-induced cardiomyopa1023 thy. J Card Fail 2017;23:476–9. [7] Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, 1024 Smith AM, et al. Genetic variants associated with cancer therapy-induced 1025 cardiomyopathy. Circulation 2019;140:31–41. 1026 [8] McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants 1027 and mechanisms. Circ Res 2017;121:731–48. 1028
Conclusions
Conflicts of Interest Acknowledgements
References
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Familial Dilated Cardiomyopathy Stacey Peters , MBBS a,b,c, Renee Johnson , PhD, MGC d, Samuel Birch , MBBS e, Dominica Zentner , PhD a,b,c, Ray E. Hershberger , MD f,g, Diane Fatkin , MD d,e,h,* a
Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, Australia Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, Vic, Australia c Department of Medicine, University of Melbourne, Melbourne, Vic, Australia d Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia e Cardiology Department, St. Vincent’s Hospital, Sydney, NSW, Australia f Divisions of Human Genetics and Cardiovascular Medicine, Wexner Medical Center, Columbus, OH, USA g Dorothy M Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA h St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia b
Received 3 October 2019; accepted 18 November 2019; online published-ahead-of-print xxx
Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only w25–40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotypephenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotypebased therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management. Key words
Familial dilated cardiomyopathy Genetics
Introduction Dilated cardiomyopathy (DCM) is a common heart muscle disease that is estimated to affect up to 1 in 250 individuals [1]. It can occur as a primary abnormality of myocardial function or in association with a myriad of cardiac and extracardiac disorders [1]. DCM is often manifested as an inherited trait in families [2], and substantial progress has been made in elucidating genetic causes of DCM using
family-based analyses. DCM is the most genetically and phenotypically heterogeneous of the inherited cardiomyopathies and this complexity has made it difficult to study from a genetic perspective [3]. In recent years, new perspectives have emerged and the boundary of what is considered to be “genetic” DCM is no longer limited to familial disease. In particular, pathogenic gene variants are thought to underlie many sporadic cases of idiopathic DCM [4] and have also been found in patients with acquired causes of DCM,
*Corresponding author at: Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst NSW 2010, Australia. Tel.: 161 2 9295 8618; Fax: 161 2 9295 877., Email: [email protected]; Twitter: @FatkinLab Ó 2019 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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including alcoholic cardiomyopathy and chemotherapyrelated cardiac toxicity [5–7]. These observations suggest that an individual’s genetic makeup is a key determinant of DCM susceptibility that needs to be considered, irrespective of family history or other identifiable risk factors. Families in which DCM is clearly inherited as a Mendelian trait remain a powerful resource for studying the genetics of this condition. Advances in sequencing technologies are now providing new platforms for genetic testing and unprecedented opportunities for elucidating the genetic architecture of DCM. Although more families are being tested around the world, interpreting the results has not been straightforward. More than 100 genes have been associated with DCM [8], and most of these have also been shown to have extensive variation in the normal population [9,10]. Distinguishing pathogenic from benign variants in such a large number of genes remains a major challenge. Despite this, a growing subgroup of genes are being identified that have distinct genotypephenotype patterns and corresponding clinical imperatives [11]. Ongoing research is urgently required to establish clinical guidelines for affected and unaffected pathogenic gene variant carriers, as well as those where no pathogenic variant is found. In this review, we will discuss topical issues in DCM, addressing questions that are relevant to the general cardiologist including: (i) who should be suspected of a possible genetic cause of DCM and what further workup may be useful, (ii) how to interpret a genetic test result and what new genes to be aware of, and (iii) how to approach management both when a gene variant is found and when it is not found, including the frequency of monitoring, best imaging modalities and lifestyle recommendations.
Clinical Presentation and Investigation Traditionally, a diagnosis of familial DCM is made when two or more first-degree relatives have “idiopathic” DCM and/or unexplained death at a young (,35 years) age [12]. However, caution is needed when assessing a patient with apparent sporadic DCM, since this may be the first presentation of disease in a kindred or represent a negative DCM family history as a consequence of small family size or variable penetrance. In this regard, a number of other features may provide clues that there could be an underlying genetic aetiology (Table 1). A detailed clinical history and examination should take place in all newly-diagnosed idiopathic DCM patients, especially young-onset cases. A comprehensive three-generation family history is necessary, particularly assessing for sudden cardiac death or heart failure. Ideally, autopsy reports or death certificates should be tracked down to corroborate information. The first and simplest investigation is an electrocardiogram (ECG). Conduction disease should be considered, including the presence of PR or QRS prolongation and atrial or ventricular ectopy. However, the most important
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Table 1 Clinical features that increase suspicion of underlying genetic disease in an index patient with DCM. Family history of DCM Family history of other cardiac features e.g. left ven-
tricular hypertrophy, valvular abnormalities, congenital heart defects, arrhythmias Family history of sudden cardiac death or cardiac arrest Young onset (,35 years) of idiopathic DCM Young onset with an acquired causal factor insufficient to explain DCM Extensive myocardial fibrosis on CMR, biopsy or autopsy in a young patient Concomitant conduction disease on ECG Concomitant early or prominent atrial arrhythmias Concomitant early or prominent ventricular arrhythmias or aborted cardiac arrest Extra-cardiac manifestations e.g. skeletal myopathy, neurological defects, lipodystrophy, dysmorphism, intellectual disability
Abbreviations: DCM, dilated cardiomyopathy; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram.
diagnostic test is a thorough echocardiogram. Dilated cardiomyopathy due to genetic or acquired causes may be indistinguishable but certain additional features may be present in the genetic forms, including increased left ventricular wall thickness, prominent left ventricular trabeculations and right ventricular or atrial chamber enlargement or dysfunction. These features are important because some DCM genes have been reported to cause other cardiac phenotypes, which can occasionally overlap in individuals and within families. Table 2 lists some of the cardiac and extra-cardiac phenotypic manifestations that have been reported in association with DCM genes. All first-degree relatives should be screened with history, exam, ECG and echocardiogram. It is worth considering that relatives may have more subtle features on ECG or echocardiography that, while not indicating a diagnosis of DCM, may still be relevant. These features include left bundle branch block, left ventricular enlargement, other chamber enlargement, isolated mildly reduced systolic function (left ventricular ejection fraction 50–55%), reduced global longitudinal strain, segmental wall motion abnormalities or hyper-trabeculation [13]. Other tests can be performed when further information is required. These include: (i) a treadmill stress echocardiogram to assess for expected augmentation of left ventricular systolic contraction during exercise, (ii) ambulatory ECG monitoring to evaluate for frequent atrial or ventricular extrasystoles, especially when there is a prominent family history of arrhythmias, cardiac arrest or sudden death, or (iii) cardiac magnetic resonance imaging (CMR), which can be useful to
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Table 2 Additional cardiac and non-cardiac phenotypic features observed with genetic variants associated with adultand paediatric-onset DCM*. Cardiac phenotypes Ventricular arrhythmias
ABCC9, ACTN2, CHKB, DES, DMPK, DSC2, DSG2, DSP, FLNC, KCNJ12, KCNJ2, KCNQ1, LMNA, MyBPHL, NKX2.5, PLN, RBM20, RYR2, SCN5A, TMEM43, TTN, ZNF9
Atrial arrhythmias/atrial fibrillation Sudden cardiac death
ABCC9, ACTN2, DMPK, EMD, FLNC, GATA4, GATA5, GATA6, KCNQ1, LMNA, LRRC10, MURC, MyBPHL, NKX2.5, RBM20, RYR2, SCN5A, TBX5, TNNI3K, ZNF9 ABCC9, ACTN2, AKAP9, CAV-3, CHKB, DES, DMPK, DSP, EMD, FLNC, KCNJ2, KCNQ1, LMNA, NKX2.5, PLN, RBM20, RYR2, SCN5A, ZNF9
Conduction disease
ACTA1, ACTN2, CAV-3, CHKB, DES, DMPK, DSP, EMD, LDB3, LMNA, MT-ND5, MURC, MyBP-HL,
Hypertrophic
ABCC9, ACAD9, ACTA1, ACTC1, ACTN2, ALPK3, ANKRD1, BAG3, CAV-3, CRYAB, CSRP3, DES, FHL2,
MYH6, MYH7, NKX2.5, SCN5A, TBX5, TNNI3K, TRPM4, ZNF9 cardiomyopathy
FHOD3, FLNC, LAMP2, MTATP6, MT-CYB, MT-ND1, MT-ND2, MT-ND5, MT-RNR2, MT-TI, MT-TK, MTTL1, MYBPC3, MyBP-HL, MYH6, MYH7, MYL2, MYL3, MYOM1, MYPN, NEXN, OBSCN, PLN, PSEN2, RAF1, TAZ, TCAP, TMEM70, TNNC1, TNNI3, TNNT2, TPM1, TTN, VCL
Left ventricular
ACTC1, ACTN2, DNAJC19, DSP, KCNQ1, LDB3, LMNA, MYBPC3, MYH7, PLEKHM2, PRDM16, RYR2,
noncompaction
TAZ, TNNT2, TPM1, TTN
Arrhythmogenic
DES, DSC2, DSG2, DSP, EYA4, LDB3, LMNA, OBSCN, PKP2, PLN, PSEN1, RBM20, RYR2, SCN5A,
cardiomyopathy
TMEM43, TTN
Restrictive cardiomyopathy
ACTC1, BAG3, CRYAB, DES, FLNC, MT-RNR1, MYBPC3, MYH7, MYL2, MYL3, MYPN, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR (amyloid)
Congenital heart disease
ACTC1, ANKRD1, CASZ1, GATA4, GATA5, GATA6, HAND1, MYBPC3, MYH6, MYH7, NEXN, NKX2.5, RAF1, TAZ, TBX20, TBX5
Brugada syndrome/early
ABCC9, AKAP9, DSG2, DSP, KCNJ2, MYH7, PKP2, RYR2, SCN5A, TRPM4
repolarization Long QT syndrome
AKAP9 (LQT11), BAG3, CAV-3 (LQT9), DNAJC19, KCNJ2 (LQT7), KCNQ1 (LQT1), RYR2, SCN5A (LQT3), TRPM4
Short QT syndrome
KCNJ2, KCNQ1
Catecholaminergic
KCNJ2, RYR2
polymorphic VT Idiopathic VT/VF
RYR2, SCN5A
Myocarditis
DSP
Pre-excitation
LAMP2, MT-ND5, MYH6
Coronary vasospasm
ABCC9
Endocardial fibroelastosis
NEBL
Non-cardiac phenotypes Congenital syndromes
ABCC9 (Cantu), ALMS1 (Alstrom), CHKB, EEF1A2, RAF1 (Noonan), TAX1BP3, TAZ (Barth), TBX5 (Holt-
Mitochondrial syndromes
Oram), UBR1 (Johansson-Blizzard) ACAD9 (Leigh syndrome), DNAJC19, MTATP6, MT-CO2, MT-CO2, MT-CYB, MT-ND1, MT-ND2, MT-ND5, MT-RNR2, MT-TE, MT-TI, MT-TK, MT-TL1, MT-T, MTTS1, RMND1, TMEM70
Congenital disorders of
ALG6, DOLK, PGM1
glycosylation Myopathy
ACTA1, ANO5, BAG3, CAV-3, CHKB, CRYAB, DES, DMD, DMPK (myotonic dystrophy 1), EMD, FKRP, FLNC, KCNJ2, LAMA2, LDB3, LIMS2, LMNA, MYH7, MYL2, MYPN, PNPLA2, POMT1, POMT2, SGCA, SGCB, SGCD, SGBG, SYNE1, TCAP, TOR1AIP1, TTN, ZNF9 (myotonic dystrophy 2)
Neuropathy Developmental impairment
BAG3 CHKB, POMT1, POMT2
Congenital cataracts
CRYAB
Cutaneous features
DSP, LMNA, PPP1R13L
Hearing impairment
EYA4, KCNQ1, MT-RNR1
Juvenile diabetes
GATA4, GATA6
Dysmorphism
KCNJ2, RRAGC
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444 445 446 Cardiac phenotypes 447 448 Lipodystrophy LMNA 449 Familial dementia PSEN1, PSEN2 450 Metabolic or storage disorders LAMP2 (Danon disease), OGT (atypical mucolipoidosis), SLC22A5 (carnitine deficiency), TTR (amyloidosis), 451 TXNRD2 (glucocorticoid deficiency) 452 453 454 Abbreviations: DCM, dilated cardiomyopathy; VT, ventricular tachycardia; VF, ventricular fibrillation. 455 *Bolded genes denote those for which there is robust evidence for DCM causation. 456 457 458 young-onset (,35 years) or associated with high-risk feaclarify functional information and exclude alternative causes 459 460 tures (Table 1, Figure 2) [25]. for DCM such as sarcoidosis, ischaemic cardiomyopathy or 461 A number of different methods for genetic testing can be infiltrative disease. CMR is also increasingly used to identify 462 used. Panel sequencing (PS), which focusses on testing a patterns of fibrosis or fat infiltration that can indicate an 463 selection of varying numbers of disease-associated genes, arrhythmogenic form of familial cardiomyopathy [14]. In the 464 remains the most widely used technique in most clinical absence of these, DCM due to any cause often results in de465 laboratories. A disadvantage of PS is that panel composition grees of mid-wall fibrosis, which can be prognostic in sudden 466 is not uniform across laboratories. Moreover, as advances in death prediction [15]. It is expected that CMR will prove 467 468 research implicate new genes, there is an ongoing need for useful in detecting early DCM in variant carriers (Figure 1), 469 panels to be redesigned. As a consequence, patient testing though most early disease features including feature470 may need to be repeated using updated panels or alternatracking-derived global longitudinal strain, T1 mapping and 471 tive methods. There has been a move in some centres to extra-cellular volume are yet to be formally studied in this 472 offer whole-exome sequencing (WES), which provides insetting. 473 formation about all genes. There are a number of pitfalls of 474 WES however, including inconsistent sequence coverage 475 476 and gaps, and studies have not consistently shown an 477 improved yield of mutation detection in adult cohorts 478 Advances in human genome sequencing technology have [26,27]. WES also does not provide information about non479 dramatically increased the scope for genetic testing in DCM. coding regions which are increasingly being suspected to 480 Until recently, genetic testing in DCM was thought to have contribute to heritable human diseases [28,29]. Whole481 limited value compared to other inherited cardiomyopathies genome sequencing (WGS) has the advantage of assessing 482 due to a low yield and modest treatment implications, and all coding and non-coding regions, as well as detecting large 483 testing was only recommended for specific genes, such as copy number variation. Emerging studies support the po- Q2 484 485 LMNA and SCN5A, that have a characteristic phenotype tential use of WGS as a first-line genetic testing method 486 (DCM and conduction-system abnormalities) and significant [27,30], although at this stage it remains mostly in the 487 complications [16]. However, high-throughput next-generaresearch domain. 488 tion sequencing has enabled the discovery of additional Regardless of the test employed, variant curation is 489 important genes, such as such as TTN, in which truncating currently the major challenge in DCM. Many family variants 490 variants are identified in w15–20% of DCM families [17], are unique and lack supporting evidence to show that they 491 and genes such as RBM20 and FLNC that can be highly 492 have function-altering effects. Further, family segregation 493 arrhythmogenic [18–20]. As the clinical utility of genetic analysis may be underpowered in small kindreds, and 494 information is increasingly recognised, a number of propenetrance and expressivity are often highly variable. The 495 fessional societies have updated practice guidelines for ACMG has devised a set of guidelines for ranking the po496 which patients need genetic testing [12,21–24]. In reality, tential pathogenicity of variants and this classification 497 testing practices differ with geographic location, access to method has become widely used in clinical practice [31]. 498 services, and reimbursement. The Heart Failure Society of Variants are classified into one of five grades: pathogenic, 499 America/American College of Medical Genetics and Ge500 likely-pathogenic, unknown pathogenicity, likely benign and 501 nomics (ACMG) guidelines recommend genetic testing in benign. Only the top two grades, “pathogenic”, and “likely502 all patients with idiopathic DCM, regardless of family pathogenic” are considered to be clinically significant and 503 history [22,23] and in the United States this is common can be used for patient management decisions and for pre504 practice. Currently, in Australia, most cardiac genetics dictive testing in relatives. The ACMG criteria take into 505 clinics will offer testing to patients with a clear pattern of account a number of factors, including whether or not a 506 familial DCM. Genetic testing is also offered by some servariant has been previously seen in affected cases and/or the 507 vices for selected patients with idiopathic DCM that is 508 general population, evidence of family segregation, and
Table 2 (continued).
Genetic Testing
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Familial Dilated Cardiomyopathy
Figure 1 Cardiac magnetic resonance imaging of genotype-positive patient with early phenotypic changes. (A) Volumetric analysis of a mid-ventricular short-axis slice in end-diastole. Endocardial, epicardial and papillary muscle contours shown. (B) Feature-tracking-derived global longitudinal strain measurement of a four-chamber cine series. (C) Late gadolinium enhanced image demonstrating the absence of the classic mid-wall enhancement often seen in established dilated cardiomyopathy (see F). (D) Native T1 mapping image of a mid-ventricular short-axis slice demonstrating interstitial expansion in the inferoseptum (black arrow). (E) Steady-state free precession-based mid-ventricular short-axis cine image in end-diastole in a normal heart. (F) Late gadolinium enhanced image in a patient with dilated cardiomyopathy.
evidence that the variant has a disease-relevant functional effect [31]. For many variants, there is insufficient information to meet the stringent criteria for pathogenicity or likely-pathogenicity, and some deleterious variants may be missed. All variants warrant periodic re-assessment as new laboratory or family evidence emerges to favour, or downgrade, initial pathogenicity classifications. This is particularly the case for “variants of unknown significance”. One strategy to reduce the level of uncertainty is to limit the list of evaluated DCM genes to a core group of disease-causing genes and to disregard variants in genes for which there is weak evidence for roles in DCM
pathogenesis. Horvat et al. [10] used a gene-centric approach to critically assess a set of 41 DCM genes represented on two gene sequencing panels and found that only 14 genes had robust evidence for disease association. Genes that are currently considered high-confidence DCM disease genes, including the “group A” genes from Horvat el al.’s study are indicated in Table 2. Due to the challenges in variant interpretation, genetic testing is ideally performed in a multidisciplinary clinic. Input from molecular cardiologists, clinical geneticists, laboratory geneticists, and genetics counsellors is usually required to analyse genetic test results and devise a plan for clinical management.
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Impact of Genetic Test Results on Family Management Scenario 1: No Pathogenic Variant is Found Despite improvements in genetic testing, 60–75% of families with clearly autosomal dominant familial DCM do not currently receive a clear genetic explanation for their condition [22,23]. Various hypotheses exist as an explanation for this including: (i) the disease-causing gene or gene variant was not detected with the technology utilised, (ii) the variant was detected but its pathogenicity was underappreciated or failed to meet the stringent criteria for pathogenicity outlined in ACMG clinical guidelines [31], or (iii) there are multiple minor variants and/or non-genetic factors contributing to disease in the family. These families should not be considered at lower risk of DCM if a single pathogenic variant is unable to be found and periodic reassessment is indicated (Figure 2). Variant interpretation is a dynamic process and may change over time with expansion of the knowledge base. Further, if additional family members are diagnosed with DCM, repeated family segregation analysis may change the interpretation of borderline variants. For clinical management, those with symptomatic DCM are treated according to standard guidelines for nonischaemic cardiomyopathy, though certain specific features may need to be considered (Figure 2). For example, if there is a strong family history of sudden cardiac death or arrhythmias, periodic rhythm monitoring is often required and earlier than usual consideration of a primary prevention implantable cardioverter-defibrillator (ICD) is warranted if high risk features are evident. If the phenotype is severe with rapid deterioration to a decompensated phase of disease, an earlier than usual referral to a heart transplant service is reasonable. For those without DCM, periodic monitoring should continue until late in life. Unfortunately, without a means to identify members at risk, all first-degree relatives need to remain in screening with ECG and echocardiography approximately every 2 years. In certain circumstances a one-off or periodic less frequent CMR could be considered.
Scenario 2: Pathogenic Variant is Present Variant-negative relatives Depending on the level of certainty that an identified variant is the primary driver of disease, genotype-negative family members may be cautiously released from screening (Figure 2). However, where there is uncertainty about the true pathogenicity of a variant, either from the laboratory or clinical side, it is our view that ongoing family monitoring may be required (Figure 2). Periodic surveillance may also be prudent for members of families with truncating TTN variants, since additional genetic or acquired factors may be present that can independently contribute to DCM risk [5–7,32]. Variant-positive, affected index patients and relatives With some exceptions (see below), familial DCM has generally been managed in line with other forms of DCM with the only additional consideration being family screening. Now, there is a growing literature on specific genotype-phenotype correlations that allows a personalised approach to be taken in some circumstances. Primarily, this refers to monitoring for unique features and timing of ICD implantation and heart transplantation. Certain DCM genes, such as LMNA and SCN5A, can cause malignant arrhythmias despite a relatively preserved ventricular ejection fraction, and routine guidelines for primary prevention ICDs may not be appropriate in these patients [11]. Patients with LMNA variants may also need early consideration of heart transplantation as they frequently have a rapidly progressive clinical course [33]. Currently, there are few instances where personalised pharmacotherapy is appropriate. An important exception is the p.R222Q SCN5A variant that has been associated with DCM and complex ventricular and atrial arrhythmias in a number of kindreds. Functional studies have shown that this variant has a gain-of-function effect on cardiac sodium channel activity, and drugs with sodium channel-blocking properties have proven to be highly effective [34–36]. For the majority of families, however, genespecific management strategies remain largely in the realm of research. Physicians managing these patients should be mindful of changes in the literature that may indicate nuanced management.
Figure 2 Flow chart for genetic testing and clinical management of an index case in whom a genetic cause of DCM is suspected. Genetic testing is recommended for patients with a family history of DCM and may also be undertaken for patients diagnosed with idiopathic DCM at a young age or with specific associated features (see Table 1). Management guidelines will vary depending on the presence or absence of a causative genetic variant and whether or not an individual has DCM. At each review, management decisions should take into account any new clinical and/or genetic information. *High risk arrhythmic features include: history of syncope, family history of sudden cardiac death, ECG with conduction block, late gadolinium enhancement on CMR, 24-hour ambulatory ECG with .1,000 premature ventricular complexes or non-sustained ventricular tachycardia, variants in highly arrhythmic genes eg. LMNA, SCN5A, FLNC, RBM20. # Features suggesting disease severity include: rapid clinical deterioration, family history of heart failure, heart transplantation or early deaths. Abbreviations: DCM, dilated cardiomyopathy; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram.
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Variant-positive, unaffected relatives Periodic monitoring is recommended for unaffected carriers of known pathogenic variants, and the type and aggressiveness of monitoring may be tailored to the specific gene or family history in some circumstances [14] (Figure 2). Carriers of variants that cause arrhythmic types of cardiomyopathy should be periodically reviewed for arrhythmic symptoms and ambulatory ECG monitoring may be included in the assessment. Some genes are associated with a more aggressive course and these may warrant more frequent follow-up. However, for most disease genes, limited data exists on the expected course, and without a clear guide of how frequently to monitor these patients we adhere to the recent American Heart Association scientific statement recommendation with an ECG and echocardiogram every 1–3 years [21]. Physicians should bear in mind that age-related penetrance is seen for many DCM gene variants so periodic monitoring should continue into later life [22]. At this stage, there are no evidence-based data for the optimal timing and indications for prophylactic pharmacotherapy in variant carriers and further research is critically needed. Acquired, Environmental, and Lifestyle Factors In all patients with DCM, regardless of whether or not a causative genetic variant has been found, there are a number of additional factors that should be considered in management, including prompt treatment of reversible arrhythmias and attention to co-morbidities, such as hypertension, coronary artery disease, diabetes, and obesity. There is increasing interest in gene-environment interactions and identification of lifestyle factors that might exacerbate myocardial dysfunction in variant carriers. Recent studies have highlighted subsets of patients with alcoholic cardiomyopathy and chemotherapy-related cardiac toxicity who carry deleterious variants in cardiomyopathy genes such as TTN [5–7]. Whether both genetic and acquired factors (“two hits”) are required for DCM manifestation, or the acquired factors acted to accelerated disease onset in genetically-predisposed individuals is unclear. In any case, identification of variant carriers in these settings may impact on patient management and has implications for clinical and genetic screening of other family members. Overall, evidence for lifestyle factor associations in genetic DCM are currently scarce, and more research is required before clear recommendations can be made. In genotype-positive females in DCM families, pregnancy should be actively recognised as a time of cardiomyopathic risk. These women should undergo pre-pregnancy counselling and serial cardiac assessment, even if baseline cardiac function is normal [37,38]. Interestingly, in cohorts of patients with peripartum cardiomyopathy, w20% cases have been found to carry deleterious cardiomyopathy gene variants [39,40], raising suspicion that much of peripartum cardiomyopathy is in fact genetically-mediated DCM.
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964 965 966 The genetics of DCM is a rapidly moving field and emerging 967 evidence is set to change the way we view and manage 968 affected patients and their families. It is important for the 969 general cardiologist to appreciate which patients should be 970 suspected as having genetically-mediated disease, what 971 further workup is required, and who should be referred for 972 973 genetic assessment. Genetic testing is evolving and, while 974 complexities in variant assessment remain, new genotype975 phenotype associations are pointing to personalised man976 agement strategies for a growing subgroup of families. 977 Nonetheless heterogeneity in genetics and phenotypic fea978 tures means ongoing uncertainty for many families, and 979 specialist cardiac genetics clinics are needed to interpret ge980 981 netic results and determine a course of action, with active 982 recognition that this will likely require future modification as 983 time and technology progress. 984 985 986 987 988 None. 989 990 991 992 993 We thank Associate Professor Andrew Jabbour from the 994 Advanced Cardiac Imaging Centre at St Vincent’s Hospital 995 Sydney, for helpful discussions. Dr Peters is supported by an 996 Australian Postgraduate Award from the University of 997 Melbourne. Dr Fatkin is supported by the National Health 998 999 and Medical Research Council of Australia, Victor Chang 1000 Cardiac Research Institute, Estate of the Late RT Hall, and 1001 Q3 the Simon Lee Foundation. 1002 1003 1004 1005 [1] Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: 1006 the complexity of a diverse genetic architecture. Nat Rev Cardiol 1007 2013;10:531–47. 1008 [2] Petretta M, Pirozzi F, Sasso L, Paglia A, Bonaduce D. Review and meta1009 analysis of the frequency of familial dilated cardiomyopathy. Am J Car1010 diol 2011;108:1171–6. 1011 [3] Bondue A, Arbustini E, Bianco A, Ciccarelli M, Dawson D, De Rosa M, et al. Complex roads from genotype to phenotype in dilated cardiomy1012 opathy: scientific update from the Working Group of Myocardial 1013 Function of the European Society of Cardiology. Cardiovasc Res 1014 2018;114:1287–303. 1015 [4] Kinnamon DD, Morales A, Bowen DJ, Burke W, Hershberger RE, DCM 1016 Consortium. Towards genetics-driven early intervention in dilated car1017 diomyopathy: design and implementation of the DCM Precision Medicine Study. Circ Cardiovasc Genet 2017;10:e001826. 1018 [5] Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar1019 Mendiguchia J, et al. Genetic etiology for alcohol-induced cardiac toxicity. 1020 J Am Coll Cardiol 2018;71:2293–302. 1021 [6] Linschoten M, Teske AJ, Baas AF, Vink A, Dooijes D, Baars H, et al. 1022 Truncating titin (TTN) variants in chemotherapy-induced cardiomyopa1023 thy. J Card Fail 2017;23:476–9. [7] Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, 1024 Smith AM, et al. Genetic variants associated with cancer therapy-induced 1025 cardiomyopathy. Circulation 2019;140:31–41. 1026 [8] McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants 1027 and mechanisms. Circ Res 2017;121:731–48. 1028
Conclusions
Conflicts of Interest Acknowledgements
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