The genetic basis for adult-onset idiopathic dilated cardiomyopathy in people of African descent

History taking and clinical examination

The first step in diagnosing DCM entails obtaining a comprehensive clinical history, physical examination, laboratory investigations, and imaging. History taking should include a three-generation family history and a pedigree [10]. Figure 2 demonstrates an example of a four-generation pedigree of a proband with IDCM. Clinical details related to the cohort, including the proband depicted in the pedigree, are described elsewhere [28].

Fig. 2figure 2

A four-generation family pedigree of a 62-year-old male (black arrow indicates proband) diagnosed with idiopathic dilated cardiomyopathy with a left ventricular ejection fraction (LVEF) of 30% at the age of 43. Squares shaded in black indicate male relatives with DCM. Females are represented with circles. Crossed-out circles and squares denote demised relatives

Clinicians should enquire about a family history of sudden cardiac death, unexplained deaths before age 50, heart transplantation, and pacemaker insertion before age 55. Furthermore, a history of death due to unnatural causes or drownings should be elicited. If a family member died due to unnatural causes, post-mortem reports should be reviewed to exclude or confirm primary or secondary causes of death [10]. History taking should be followed by a thorough clinical examination that includes a neurological examination focused on identifying neuromuscular diseases such as muscular dystrophy, which may manifest as muscle wasting, contractures of the elbows, spine, and Achilles tendons [29].

Electrocardiogram

Various electrocardiographic abnormalities may be found in patients with DCM, including a prolonged PR interval, evidence for ventricular hypertrophy, pathological Q waves, or bundle branch block [30,31,32]. In addition, poor prognostic factors on ECG include atrial fibrillation and a left bundle branch block [32].

Echocardiogram

An echocardiogram is mandatory to confirm ventricular dilatation and calculate the LVEF, which may guide the selection of appropriate heart failure therapy. In addition, features of cardiac remodelling, which include increased left atrial size, functional mitral insufficiency, alteration of diastolic function, and involvement of other chambers, should be elicited as these features are also associated with an unfavourable prognosis [32, 33]. Speckle-tracking echocardiography may also help to identify asymptomatic patients with left ventricular systolic dysfunction before they manifest with an overt DCM phenotype [34].

Laboratory tests

Laboratory biochemical tests are an integral part in the clinical workup of patients suspected to have IDCM. These may identify DCM’s endocrine, infectious, and haematological causes. Detecting micronutrient deficiencies such as selenium or thiamine may suggest malnutrition, which is strongly associated with alcohol misuse (Fig. 3). Abnormally high serial cardiac troponin and creatine kinase serum levels may indicate an acute myocyte injury due to myocarditis. Thyroid stimulating hormone and thyroxine levels should be assessed to exclude hypothyroidism or hyperthyroidism. Low calcium levels may indicate underlying chronic hypocalcaemia, while elevated iron levels may suggest underlying iron overload. When clinically suspected, bacterial and fungal infections should be excluded by performing blood cultures. Furthermore, a significantly elevated brain natriuretic peptide level has been reported to suggest a poor prognosis in patients with DCM [35,36,37].

Fig. 3figure 3

Causes of dilated cardiomyopathy that should be considered after excluding coronary artery disease

Coronary angiography

Coronary angiography is currently the gold standard for evaluating coronary epicardial vessels’ atherosclerotic disease. Therefore, all patients with DCM should ideally be referred for a diagnostic coronary angiogram to exclude coronary artery disease. Furthermore, this test is mandatory since the therapeutic approach varies in patients with ischaemic and non-ischaemic cardiomyopathy.

Cardiovascular magnetic resonance imaging

Magnetic resonance imaging is crucial for excluding infiltrative conditions such as sarcoidosis and amyloidosis. In addition, the visualisation of gadolinium enhancement on late images may indicate underlying fibrosis. Several research studies have reported an association between the visualisation and burden of late gadolinium enhancement (LGE) and all-cause mortality in DCM [38,39,40,41].

Endomyocardial biopsy

An endomyocardial biopsy provides a definite histological, immunohistochemistry, and molecular evaluation of myocardial tissue [11]. It is indicated in patients suspected to have acute myocarditis or chronic inflammatory cardiomyopathy. The evaluation of endomyocardial biopsy samples of DCM patients may show nonspecific histopathological signs such as hypertrophy and vacuolar changes of myocytes and fibrosis [42]. Although invasive, the risk of complications associated with an endocardial biopsy is low, with 11% of patients experiencing atrioventricular block [42].

Endomyocardial biopsies should be considered if the test will likely alter the therapeutic management of patients, mainly if conditions such as sarcoidosis, giant cell myocarditis, eosinophilic myocarditis, or hemochromatosis are considered differential diagnoses. Strategies that could improve access to myocardial biopsy, particularly in low- and middle-income countries (LMIC), include the implementation of referral pathway protocols that prioritise the performance of biopsies in these patients, ensuring that personnel are adequately trained, as well as increasing the number of available catheterisation laboratories.

Genetic testing

Pre-test genetic counselling should be provided to DCM patients and their families. A detailed family history should be taken, and the possible findings and implications of genetic results should be explored during the counselling session. Defining terminology such as “pathogenic mutations, variants of uncertain significance and benign genetic variants” should be explained [8, 13]. Post-test counselling should focus on interpreting results, discussing reproductive risk, and the need for cascade family testing [13, 28].

Cardiomyopathy gene testing is still not widely available in most LMICs. However, diagnostic testing should be performed in carefully phenotyped patients with evidence of disease. In contrast, predictive testing is recommended in asymptomatic individuals (usually family members of an individual with a known DCM mutation) to predict the future risk of disease [43]. Currently available genetic tests involve sequencing a single gene or an individual variant, cardiomyopathy gene panel sequencing, whole-exome sequencing, and whole-genome sequencing [44].

Sequencing a single gene or individual variant should be considered a confirmatory test in a family member with a proband carrying a pathogenic/likely pathogenic variant detected through other techniques. Although this approach is cost-effective, it is not appropriate for diagnostic testing in a proband from another family with DCM where the causal mutation has not yet been identified [44, 45]. Cardiomyopathy gene panel sequencing involves sequencing the coding regions of several cardiomyopathy genes simultaneously in a single experiment. The diagnostic yield is higher. However, this test may not capture non-coding variants [13].

Whole-exome sequencing involves the analysis of a sequence of the entire coding region of the human genome. Limited non-coding regions may be included, but much of the non-coding DNA is not analysed. Whole-exome sequencing is not limited to genes previously linked with disease, thus enabling the potential to identify novel variants in new genes of interest. However, there is also a higher likelihood of identifying a variant of uncertain significance with whole-exome sequencing, and these usually need further investigation or careful explanation to patients as to their unknown implications [46]. In contrast, whole-genome sequencing captures both coding and non-coding variants, including deep intronic variants. Although more expensive, whole-genome sequencing will capture all variants and can be used to calculate polygenic risk scores for multifactorial causality of DCM and to report pharmacogenetic variants [47]. If a causal genetic mutation for monogenic DCM is identified, cascade screening of family members should be implemented, where a specific mutation rather than a gene panel is evaluated.

Genetic testing within the African context is challenging, partly due to the diverse genetic makeup of populations within the continent, making the possibility of identifying a variant of uncertain significance higher [48]. Furthermore, currently available DCM gene panels could be limiting in the African context as the diagnostic yield may be lower since African-specific DCM-causing genes (should they be present) have not yet been identified. In addition, the current gene panels are based on DCM patients who are primarily not of African descent. Figure 4 summarises an approach to genetic testing in a proband with DCM.

Fig. 4figure 4

An approach to genetic testing in a proband with dilated cardiomyopathy. Diagram modified from Tayal et al. [10]. DCM dilated cardiomyopathy, ECG electrocardiogram, ICD implantable cardioverter defibrillator, LP likely pathogenic, LV left ventricular, MRI magnetic resonance imaging, P pathogenic, VUS variant of uncertain significance

Differential diagnosis

Diagnosing DCM may be challenging in most LMICs and other remote regions without access to diagnostic modalities such as coronary angiography or cardiovascular MRI. In such scenarios, the diagnosis is generally made on clinical grounds. The higher prevalence of infectious diseases in sub-Saharan Africa makes viral myocarditis highly likely. As such, clinicians faced with patients presenting acutely with the clinical syndrome of heart failure should routinely evaluate and monitor serum troponins, creatine kinase-MB levels, and viral antibody titres to exclude viral myocarditis. The viral antibody titre tests may include coronavirus, enterovirus, HIV, cytomegalovirus, Epstein-Barr virus, adenovirus, human herpes virus 6, parvovirus B19, hepatitis, and influenza virus antibodies [49].

A genetic aetiology should be considered in females with idiopathic cardiomyopathy in the peripartum phase [50,51,52,53]. A discussion on the genetic basis of peripartum cardiomyopathy is beyond the scope of this manuscript, and the reader is referred to literature published elsewhere [54].

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