Genetics of inherited cardiomyopathies in Africa
Review Article on Cardiovascular Diseases in Low- and Middle-Income Countries

Genetics of inherited cardiomyopathies in Africa

Gasnat Shaboodien1,2, Timothy F. Spracklen1,2, Stephen Kamuli1,2, Polycarp Ndibangwi1,2, Carla Van Niekerk1,2, Ntobeko A. B. Ntusi1,2,3

1Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, 2Department of Medicine, 3Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

Contributions: (I) Conception and design: G Shaboodien, NA Ntusi; (II) Administrative support: C Van Niekerk; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: TF Spracklen, S Kamuli, P Ndibangwi, Van Niekerk; (V) Data analysis and interpretation: G Shaboodien, TF Spracklen, S Kamuli, P Ndibangwi, NA Ntusi; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Associate Professor Gasnat Shaboodien. Director, Cardiovascular Genetics Group, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa. Email: Gasnat.Shaboodien@uct.ac.za.

Abstract: In sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCDs) is rising disproportionately in comparison to the rest of the world, affecting urban, semi-urban and rural dwellers alike. NCDs are predicted to surpass infections like human immunodeficiency virus, tuberculosis and malaria as the leading cause of mortality in SSA over the next decade. Heart failure (HF) is the dominant form of cardiovascular disease (CVD), and a leading cause of NCD in SSA. The main causes of HF in SSA are hypertension, cardiomyopathies, rheumatic heart disease, pericardial disease, and to a lesser extent, coronary heart disease. Of these, the cardiomyopathies deserve greater attention because of the relatively poor understanding of mechanisms of disease, poor outcomes and the disproportionate impact they have on young, economically active individuals. Morphofunctionally, cardiomyopathies are classified as dilated, hypertrophic, restrictive and arrhythmogenic; regardless of classification, at least half of these are inherited forms of CVD. In this review, we summarise all studies that have investigated the incidence of cardiomyopathy across Africa, with a focus on the inherited cardiomyopathies. We also review data on the molecular genetic underpinnings of cardiomyopathy in Africa, where there is a striking lack of studies reporting on the genetics of cardiomyopathy. We highlight the impact that genetic testing, through candidate gene screening, association studies and next generation sequencing technologies such as whole exome sequencing and targeted resequencing has had on the understanding of cardiomyopathy in Africa. Finally, we emphasise the need for future studies to fill large gaps in our knowledge in relation to the genetics of inherited cardiomyopathies in Africa.

Keywords: Inherited cardiomyopathy; Africa; genetics; next generation sequencing; review


Submitted Jul 08, 2019. Accepted for publication Sep 29, 2019.

doi: 10.21037/cdt.2019.10.03


Introduction

With increased globalisation and modernisation, different regions are becoming progressively more interconnected through the movement of people, goods, capital and ideas. The health systems in sub-Saharan Africa (SSA) (Table S1) are consequently facing challenges imposed by a unique quadruple burden of increasing noncommunicable diseases (NCDs), persisting morbidity and mortality from communicable diseases, high maternal and infant mortality, and trauma and interpersonal violence (1-3). Combine these factors with changes in lifestyle, an ageing population and a healthcare environment that is marked by limited resources, short supply of well-equipped screening facilities, late diagnosis, and suboptimal care at primary, secondary, tertiary and quaternary levels, as well as a paucity of national level data on disease trends (4,5), it is clear that SSA is facing a crisis in healthcare. The Global Burden of Disease study reported cardiovascular diseases (CVD) as the leading cause of mortality worldwide, and the second commonest cause of mortality after the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) in SSA (6). CVD are predicted to surpass HIV/AIDS and other infections as the leading cause of death in SSA over the next decade (7,8). The most common underlying cause of HF in high-income countries (HICs) is coronary artery disease (CAD) (9), but in SSA, the predominant causes are hypertension, cardiomyopathy, rheumatic heart disease (RHD) and pericardial disease (1,10,11).

Table S1
Table S1 Abbreviations
Full table

Remarkable progress over the past few decades has been made in the field of CVD, guided in particular by the continuously evolving classification systems for HF and cardiomyopathy. The role of cardiomyopathy in heart failure and as a healthcare burden in Africa has been reviewed elsewhere (1,4,12,13). This review investigates the molecular genetics and incidence of the cardiomyopathies across the African continent with particular focus on the inherited cardiomyopathies such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), restrictive cardiomyopathy (RCM) and left ventricular noncompaction (LVNC) (Table 1).

Table 1
Table 1 Definitions for the inherited cardiomyopathies
Full table

Cardiomyopathies

The cardiomyopathies (14) (Table 1) have been described as a group of morphofunctional cardiac disorders that are classified into familial/genetic and non-familial/non-genetic causes and are the major cause of sudden cardiac death (SCD) and HF in childhood and early adulthood. Cardiomyopathies are also associated with extensive genetic heterogeneity. Pathogenic mutations have been reported in cardiac sarcomere protein genes, cytoskeletal protein genes and nuclear envelope protein genes (15). There is increasing evidence that the clinical entities of DCM, HCM, ACM, RCM and LVNC share some disease genes with each other (16-18). Most cases occur sporadically, possibly pointing to de novo mutations.

Globally, the prevalence of cardiomyopathy is estimated at 2.5 million cases, an increase of 27% in 10 years (19) and can be caused by myocarditis, toxins, endocrinopathies, nutritional deficiencies, drugs and genetic abnormalities. In low- and middle income countries (LMICs), the prevalence of cardiomyopathy is considered to be higher than in HICs; but as no population-based incidence or prevalence studies of HF or cardiomyopathy have been published, most of the available epidemiological data are gathered from hospital-based studies, often with variable application of established diagnostic criteria (20). In Southern Africa, hospital-based studies reported the highest prevalence of cardiomyopathy in SSA at 40.2%, compared to East Africa where the prevalence was lowest at 18.2% (21-24). Agbor et al. reported that the risk of developing congestive HF is ~30% higher in black Africans compared to their white counterparts, a finding that is not explained by the confounding variables of hypertension or socioeconomic factors (12). Treatment of patients with cardiomyopathies in LMICs is generally suboptimal as few patients take evidence-based combinations of diuretics, beta-blockers, angiotensin converting enzyme inhibitors (ACE-Is) and mineralocorticoid receptor antagonists (MRAs). Subsequently, mortality is high for African patients with HF (22,23,25,26). Cardiomyopathy is an endemic form of NCD of high importance to the poor majority in SSA – and a locally relevant unmet need for research (24,27).

To identify incidence studies for the inherited cardiomyopathies in Africa, we searched the PubMed, Web of Science, and Scopus databases for studies reporting on cardiomyopathy originating from Africa, including all referral-based case series, hospital and research studies. Studies reporting only on secondary or acquired causes of cardiomyopathy were excluded. The search produced 92 studies reporting on the incidence rates of DCM, HCM, ACM, RCM and LVNC in Africa (Table S2); these are discussed below. We are aware that hospital-based studies are inherently biased due to non-random sampling techniques and that many of the selected studies’ denominators are small and could reflect a strong selection and referral bias which may be misleading, however, they are included in this review for completeness. We reviewed the population size of the various African countries as well as the cardiologist-to-population ratio (where available) and found that some hospitals had catchment areas ranging from a few thousand to several million people.

Table S2
Table S2 Studies on the incidence of cardiomyopathy in Africa
Full table

Dilated cardiomyopathy

DCM is the most common cardiomyopathy, accounting for approximately 55% of cardiomyopathies (14), but as the prevalence rates for DCM has yet to be determined, we searched the literature for studies reporting on the incidence of DCM in Africa and found 52 articles (Tables 2,S2), most of which were hospital-based studies. More than 67% of these studies were from Western and Eastern Africa, where the top two major causes of mortality from NCDs are documented as ischaemic heart disease and stroke. The largest of these studies occurred in Ethiopia (n=6,275) and Malawi (n=3,908) where 477 and 720 patients were reported to have DCM, respectively [Table S2 (14,28)]. The high incidence rates of DCM are supported by many studies from various regions of Africa (Table S2).

Table 2
Table 2 Incidence of cardiomyopathy in the five regions in Africa (Northern, Southern, Central, Eastern and Western)
Full table

Genetics of DCM

Up to 50% of DCM cases are familial, with many disease-causing gene mutations described (29). The genetic forms of DCM usually result from mutated genes encoding 2 major subgroups of proteins: cytoskeletal and sarcomeric proteins (15,30). In 20–50% of cases, DCM is inherited in an autosomal dominant manner, and nearly 60 different genes are involved (31). Among them, involvement of the sarcomeric gene, TTN is most prevalent (40%), followed the nuclear lamin gene LMNA (10%) (32-34). Mechanistically, cytoskeletal proteins are cause defects of force transmission, resulting in the DCM phenotype, whereas defects of force generation have been speculated to be associated with sarcomere protein-induced DCM (35,36). Mutations in desmosomal genes cause DCM and other forms of cardiomyopathy, and disrupt the links between the intercalated disk, Z-disk, and sarcomere (15).

To date, there is no published, large multicentre study of families in Africa whose members have been systematically clinically screened for DCM and have also undergone whole exome or genome sequencing to identify a possible genetic cause. We reviewed the available literature on the genetics of DCM in Africa and identified 9 studies (Table 3) that used a genetics approach in DCM cohorts. Six of the initial genetics studies (5 performed in South Africa) carried out from 1999 to 2010 aimed to determine the association of specific polymorphisms with differences in left ventricular (LV) systolic performance or internal LV dimensions; changes in LV ejection fraction (LVEF); LVEF and LV end diastolic diameter (LVEDD); risk of HF, or severity or risk of progression of HF in high-risk DCM, with mixed findings (37-42). At least half of these studies found positive associations with LVH, improved LVEF and disease risk. The other genetics studies investigated the role of candidate genes in DCM. A study from our group screened the complete PLN gene in a cohort of 95 DCM patients and found the previously reported PLN p.R9C mutation in a South African family with severe autosomal dominant DCM (44). As with a previous report, the PLN p.R9C mutation was detected in an individual with acute onset of DCM at the age of 21 years, leading to heart transplantation at 22 years of age (28). Even though mutations in PLN have been associated with DCM (68-70), HCM and ACM in North America and Europe, the role of PLN in Africans with cardiomyopathy is unclear. Ours was the first report of a PLN mutation on the African continent and, in a screen of 315 patients comprising DCM, HCM, ACM and peripartum cardiomyopathy (PPCM), the PLN gene appeared to be a rare cause of cardiomyopathy in Africans (44). Finally, the only DCM study to have used NGS on the African continent was carried out in 2018 in a Moroccan family (32) where targeted resequencing was used to screen the DNA of five family members for 50 cardiomyopathy genes. The investigators found a previously reported pathogenic LMNA p.R54C mutation as the cause of disease within this family.

Table 3
Table 3 Genetic studies of inherited cardiomyopathies in Africa
Full table

The few studies that have emerged from Africa on the genetics of DCM are vastly inadequate and highlight an urgent need for comprehensive genetic testing of all DCM patients in Africa in order to understand the basic genetic milieu and to be able to treat patients accordingly.


Hypertrophic cardiomyopathy

HCM is considered a common form of cardiomyopathy in European and North American cohorts (8). A study from our group reported that while the annual mortality rate of 2.9% was high and the overall survival of 74% at 10 years was low compared to other series of patients with HCM (71), the survival rate was comparable to age- and gender-matched members of the South African population (61).

HCM was historically thought to be rare among Africans (46,47,50,52,72). This impression was reinforced by a Tanzanian study that found HCM to occur in 0.2% of 6,680 unselected echocardiograms (73) however, echocardiographic studies from Ghana (74) have reported HCM to be the third commonest cardiomyopathy after DCM and endomyocardial fibrosis (EMF) (10) and in Ethiopia, HCM accounts for 34% of all cardiomyopathies diagnosed on echocardiography (75). However, there is little information on the incidence, prevalence, clinical features, genetics and outcome of HCM from the African continent, with a few publications reporting on HCM-causing mutations in South Africans of northern European descent and mixed ancestry (46,47,50,52). In 2016, we reported on the first prospective investigation of the clinical characteristics, genetics and outcome of HCM in Africans. We found HCM to occur predominantly in men, with a young age of onset, including black Africans, and with a positive family history of HCM in the majority. The major symptoms and complications were similar to those reported in North American, Middle Eastern and Asian studies (61,71).

In order to obtain an estimation of the incidence of HCM in Africa, we searched the literature for studies reporting on the incidence of HCM in Africa and found 24 articles (Tables 2,S2), most of which were hospital-based studies. The largest of these studies were from Tanzania (n=6,680), Ethiopia (n=6,275) and Malawi (n=3,908) where 134, 21 and 3 patients were reported to have HCM, respectively (73,76,77). The very wide distribution ranges for the incidence rates of HCM in Africa could also be explained by small study sizes, limited resources, short supply of well-equipped screening facilities, late diagnosis and underdiagnosis.

Genetics of HCM

HCM is a monogenic disorder caused by mutations in genes that encode sarcomere proteins. Incomplete penetrance is seen within families and is hypothesised to be due to additional environmental, genetic or epigenetic factors. Genetic testing sensitivity for familial HCM is 50–60% (78,79). Of individuals with known mutations, 70% harbour mutations within either the β-myosin heavy chain (MYH7) or myosin-binding protein C (MYBPC3) genes. MYH7 mutations are associated with high disease penetrance and moderate to severe LV hypertrophy (LVH), while MYBPC3 mutations manifest in mid- to late-adulthood with mild to moderate LVH and a relatively good prognosis. Troponin T2 gene (TNNT2) mutations account for around 5% of disease, with a high incidence of SCD even with minimal LVH (14). Despite >1,400 known mutations, the downstream cardiomyocyte metabolic effects are largely similar, characterised by an increased energetic cost of contraction and reduced cycling of ATP, resulting in heightened cardiac contraction and faulty relaxation, and reduced overall sarcomeric power (61,80,81).

We reviewed the available literature on studies reporting on the genetics of HCM in Africa and identified 18 studies: 15 conducted in South Africa and one in Egypt, one in Tunisia and another in Morocco (Table 3); only 3 of these studies employed NGS technology (59,61,62). These studies gave new insights into the functional effects of genetic mutations on disease mechanism and pathogenesis of HCM in the South African families. In 1993, a group in South Africa performed the first candidate gene study on the African continent in an HCM cohort of five unrelated index cases of mixed ancestry. This relatively small pioneering HCM study identified the first African index case with a mutation in MYH7 (p.Arg403Trp) and led the way in genetic discoveries in HCM for the next two decades. They reported nine mutations (six of which were novel) in a South African HCM population consisting of mixed ancestry and white individuals of northern-European descent: MYH7: p.Arg249Gln, p.Arg403Trp, p.Ala797Thr (novel), p.Gly499Lys (novel), p.Arg719Gln; TNNT2: p.Arg92Trp (novel); MYBPC3:Arg654His (novel), Δc756 (novel), Val896Met (novel). The group also found that none of the other HCM disease-associated mutations that had been reported worldwide occurred in their South African HCM cohort. Further candidate gene screens detected the presence of the MYH7 p.Arg403Trp, MYH7 p.Ala797Thr and cTNNT2 p.Arg92Trp mutations in 1, 8, and 4 probands, respectively. This was very different from the profiles seen in most North American and European referral centres, where numerous “private” MYH7 mutations are reported to account for ~40–70% of HCM (61).

Cognisant of the history of South Africa and colonisation by Europeans in the 17th century, they hypothesised that the recurring mutations were due to founder mutations. Founder-gene effects are not uncommon in South Africa, especially among the Afrikaner subgroup of the white population (82-87). These founder effects are probably due to bottlenecks in gene transmission, caused by rapid expansion of the white population in the Western Cape after the initial colonisation by the Dutch in 1652 (82,83). The mixing of genes from the Europeans and the indigenous people of South Africa like the Khoikhoi, the San and later also with the Xhosa people, and indentured slaves from Malaysia led to the origin of the mixed ancestry population “Cape Coloureds” of South Africa, known to be the most genetically admixed population in the world. Linkage studies performed in families carrying these recurring mutations allowed for tracing of their origin to three common ancestors in the Western and Eastern Cape provinces, where the MYH7 p.Ala797Thr mutation accounts for 25% of the HCM cases, cTNNT2 p.Arg92Trp is the causative mutation in 15%, and MYH7 p.Arg403Trp in 5% of affected individuals. Collectively, the 5 MYH7 mutations (Arg249Gln, p.Arg403Trp, p.Glu499Lys, p.Arg719Gln, p.Ala797Thr) were responsible for disease in 37.5% of HCM cohorts in the South African sub-populations studied. Reports showed that the MYH7 mutations have distinct cardiac functional effects in HCM patients without hypertrophy (88). Specifically, the MYH7 p.Arg403Trp mutation is a strong predictor of the development of LV dilation and systolic and diastolic dysfunction in later life (50,89). Milder phenotypes of the MYH7 mutations may account for the high presence of these founder mutations within the HCM cohorts in South Africa. Long-term follow-up of founder families with HCM showed that all carriers of the TNNT2 p.Arg92Trp mutation (who typically have no cardiac hypertrophy during their youth) developed hypertrophy after the age of 35 years. The distinct functional effect of the TNNT2 p.R92W mutation resulted in a relative increase in systolic functional parameter and an abnormal blood pressure response to exercise occurred more commonly in HCM patients with the TNNT2 p.R92W mutation than in those with MHY7 mutations (45). These observations may be relevant to the understanding of the high mortality associated with TNNT2 p.R92W mutation despite minimal evidence of cardiac hypertrophy (50). Despite the large percentage of founder mutations, there were also many novel mutations, which led to the researchers proposing that the profile of HCM-causing mutations would be unique in different geographic areas and that it is the result of numerous nascent mutations.

Advancements in genetic technology led to the first NGS study on an HCM cohort conducted on the African continent. In the study by Jaafar et al., targeted resequencing was used to screen nine known HCM genes in a cohort of 45 Tunisian patients (59). They reported a 27% mutation detection rate, predominantly in MYBPC3 and MYH7 although FLNC and MYL3 mutations were also found. This study pointed to the heterogeneous genetic background of Tunisians, but founder mutations were not present at a high rate among Tunisians. The other NGS study by our group showed the same basic genetic yield of 29% (61) with both studies showing a much lower rate than the global frequencies for HCM. These few studies have made some important contributions to understanding the genetic basis of HCM in Africa, but what is clear is that many more African genetics studies need to be conducted to provide important insights into about the genetics of HCM.


Arrhythmogenic cardiomyopathy

ACM is an inherited disease of cell-to-cell junctions resulting in electrical instability and risk of SCD. Currently, ACM is the only cardiomyopathy whose diagnostic criteria incorporate the presence of a known genetic mutation (90). ACM has both a higher incidence and severity of disease in male patients (14,91-93). As there are no prevalence data available on ACM in Africa, we aimed to obtain an estimate by searching the literature for studies reporting on the incidence of ACM and found 3 hospital-based studies (Tables 2,S2) (94-96). The largest study occurred in Tanzania where 815 adult CVD patients were screened but only 2 patients were reported to have ACM (71).

Genetics of ACM

To date, 15 genes have been reported to cause ACM (97-101). Amongst these, 5 causal desmosomal genes have been identified, including plakophilin 2 (PKP2) (102), desmoplakin (DSP) (103), desmoglein-2 (DSG2) (104) and desmoscollin-2 (DSC2) (105), and junctional-plakophilin (JUP) (106). Together, these genes account for only 50% of ACM, so it is likely that other causal genes are yet to be identified (81,107). The genetics of ACM have been suggested to be more complex than the simple monogenic heritability as in some cases patients with ACM have more than 1 mutation in the same gene (compound heterozygosity) or in another modifier gene (digenic heterozygosity) (108). Analyses of first- and second-degree relatives of patients with ACM suggest that up to 50% of ACM cases are familial. ACM is most commonly inherited as an autosomal dominant trait with incomplete penetrance (98,99,109), although 2 autosomal recessive forms have been described (110). As penetrance is incomplete, genetically affected relatives often demonstrate variable and mild (or no) phenotype and the prevalence of familial disease is often underestimated in clinical practice (91,97,111). Genetic testing for ACM using a larger cardiomyopathy panel may identify non-desmosomal genes with pathogenic variants. Similarly, desmosomal gene pathogenic variations have also been identified in patients diagnosed with DCM (16). Exercise has a well-established role in the pathogenesis of desmosomal cardiomyopathies, and recognition of a desmosomal gene mutation can help to determine optimal exercise recommendations (112,113).

Genetically determined disruption of the integrity of the intercalated disk is a key factor promoting the development of ACM and SCD. Loss of desmosomal integrity can substantially affect gap junctions, sodium channel function and electrical propagation, thereby promoting ventricular arrhythmias in the absence of overt structural damage (114,115) and thus providing an overlapping phenotype (cardiomyopathy plus arrhythmias) because of disruption of 2 “final common pathways” (desmosome and ion channel) (116,117).

We reviewed the available literature on the genetics of ACM in Africa and identified 4 studies (3 conducted in South Africa by our group) (Table 3) (63-66) that used a molecular genetics approach to determine the cause of disease in ACM cohorts: the first ACM study in Africa was done in 2006 on a large South African family where linkage was used to narrow the region but no disease-causing mutation was found (63). Twenty years later, and with the advent of new technologies such as NGS, we used WES on 2 cousins (in the three-generation family studied in 2006) with ACM. We identified a novel mutation in CDH2 (p.Gln229Pro) as the cause of disease in this family, as well as a second CDH2 (p.Asp407Asn) variant after screening a cohort of 73 genotype-negative ACM probands. In 2009, our group reported a candidate gene screening of the PKP2 gene and found 7 mutations in 25% of the ACM cases, 5 being novel. We reported on the novel PKP2 p.Arg388Trp mutation which occurred in 4 white South Africans who shared a common haplotype, prompting us to suggest a possible founder mutation. Finally, in 2017, Choung et al. reported the ACM-related loss of a young mother and athlete from East Africa in the third trimester of an uneventful pregnancy. A cardiac panel with known disease genes was used for screening; however, a heterozygous variant of unknown significance (VUS) was found in MYBPC3, so no genetic cause was found. Two of these 4 studies on ACM on the African continent have reported novel, private mutations and highlights the possibility that SSA could provide some very important insights into ACM and identify other possible disease mechanisms which might shed some light on the different pathways that lead to ACM.


Restrictive cardiomyopathy

RCM represents a very small fraction (<5%) of all cardiomyopathies in HICs, both in paediatric (118) and in adult populations, although prevalence may be more common in certain regions including Nigeria, Malawi, Ivory Coast, Mozambique and Uganda (119). Endomyocardial fibrosis (EMF) is a common cause of RCM causing impaired filling of one or both ventricles. Some reports suggest clinical overlap between RCM and HCM (15,120,121). The aetiology of EMF remains poorly understood, though evidence points towards eosinophilic inflammation and fibrosis possibly related to parasitic infections (25,122). As there is no prevalence data available on RCM in Africa, we searched the literature to obtain an estimate for the incidence of RCM and found 8 articles (Tables 2,S2). The largest studies occurred in Ethiopia (n=6,275) and Malawi (n=3,908) but only 7 and 3 patients were reported to have RCM, respectively (14,28).

Genetics of RCM

Familial RCM usually has autosomal dominant inheritance, but autosomal recessive, X-linked and mitochondrial-transmitted disease occurs. Most of the identified genes encode sarcomere or Z-disk proteins, such as TNNI3, TNNT2, MYH7, ACTC1, TPM1, MYL3, and MYL (35,123) (Table 3). Z-disk protein-encoding genes, including MYPN, TTN, and BAG3, have also been identified (97,99,101,124,125). Missense variants in DES have been identified in several families with desmin-related myopathy, which can present with RCM, with or without skeletal myopathy and/or atrioventricular block. A recent study identified a pathogenic variant in 60% of subjects, primarily occurring in genes known to cause HCM (126). Family members were frequently identified with HCM or HCM with restrictive physiology. Transthyretin (TTR) is a gene is associated with amyloid-related RCM (125) and pathogenic variants in the TTR gene needs to be differentiated from other forms of RCM due to the age demographic in which this occurs, the slowly progressive nature of this disease, and therefore different management strategies (127,128). The TTR allele p.Val142Ile has been found in 10% of African Americans older than 65 years of age with severe congestive HF (112).

We reviewed all the available literature on studies reporting on the genetics of RCM in Africa and identified only 1 study (Table 3). Mouton et al. reported the first, and only, study on the genetics of RCM in Africa in 2015. They hypothesised that mutations in TNNI3 could underlie HCM with restrictive features in 115 HCM probands. They found a novel disease-causing TNNTI3 p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy, often below the typical diagnostic threshold for HCM. This result is not surprising though, as it is well established that genes of the sarcomere can cause HCM, DCM and RCM (67). However, this 1 available RCM study in Africa highlights the urgent need for additional genetic studies on this continent that will shed more light on RCM disease pathogenesis in this setting.


Left ventricular noncompaction

LVNC is a heterogeneous myocardial disorder characterised by prominent trabeculae that are most evident in the LV apex, intratrabecular recesses, and LV myocardium with 2 distinct layers: compacted and noncompacted myocardium (97,99,129,130). The LVNC phenotype may be observed in conjunction with all other cardiomyopathy phenotypes (112), so considerations related to genetic testing should always be directed by findings of a cardiomyopathy (or other cardiovascular) phenotype (131,132). Our search yielded 5 articles from Africa on LVNC (Tables 2,S2) with low incidence rates. The largest study occurred in Sudan (n=4,500) but only 22 patients were reported to have LVNC (11).

Genetics of LVNC

LVNC has been associated with mutations in >40 genes and a number of chromosomal defects (133). The former includes genes involved in muscular dystrophies (e.g., DMD, LMNA, DMPK), congenital and hereditary myopathies (e.g., MYH7, RYR1, TPM1, TAZ) and metabolic/mitochondrial disorders (e.g., LAMP2, GBE1, SDHD, HADHB) (134-137). Notably, mutations in sarcomere genes (e.g., MYH7, MYBPC3) are identifiable in a significant proportion (around 30%) of isolated LVNC. However, causation has yet to be established, with attendant variable recommendations for genetic testing. LVNC is familial in 30–50% of cases, with autosomal dominant (e.g., MYH7), autosomal recessive, X-linked (e.g., the multisystem Barth syndrome resulting from a mutation in TAZ) and maternal (mitochondrial) inheritance patterns described. In view of this, first-degree relatives of index patients should undergo echocardiographic screening (14,133). We did not find any reports on the genetics of LVNC in African countries.


Conclusions

Africa is dealing with the colliding epidemics of communicable disease and rapidly expanding epidemics of NCDs, which include HF. Our review has highlighted the large gaps in knowledge on inherited cardiomyopathies, particularly in SSA. Health systems throughout Africa are overburdened and understaffed and in desperate need of improvement. If the current trajectory is not altered, Africa will continue to face an increase in the burden of CVD and patient mortality will continue to escalate.

We have summarised the data on the molecular genetic underpinnings of cardiomyopathy in Africa. Little is known about the aetiology and outcome of cardiomyopathy, especially related to the inherited cardiomyopathies: DCM, HCM, ACM, RCM and LVNC. While many genes have been identified as the cause of inherited cardiomyopathies outside of Africa, there have been relatively few publications on genetics of cardiomyopathies in SSA (4,27,138,139). Over the years though, genetics has moved from single gene screens to next generation sequencing (NGS) where entire genomes can now be sequenced by small laboratories and researchers are able to study biological systems at a level never before possible. NGS creates a single platform for the molecular genetic screening of the cardiomyopathies of interest in Africa and will go a long way to filling the large gaps in knowledge on the genetics of the inherited cardiomyopathies in Africa.


Acknowledgments

Funding: Drs Shaboodien and Ntusi gratefully acknowledge support from the National Research Foundation and the Medical Research Council of South Africa. In addition, Dr Ntusi also acknowledges support from the Harry Crossley Foundation and Lily & Ernst Hausmann Trust.


Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Ntobeko A. B. Ntusi) for the series “Cardiovascular Diseases in Low- and Middle-Income Countries” published in Cardiovascular Diagnosis and Therapy. The article was sent for external peer review organized by the Guest Editor and the editorial office.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt.2019.10.03). The series “Cardiovascular Diseases in Low-and Middle-Income Countries” was commissioned by the editorial office without any funding or sponsorship. NABN served as the unpaid Guest Editor of the series, and acknowledges funding from the South African Medical Research Council, National Research Foundation, the Harry Crossley Foundation and the Lily and Ernst Hausmann Trust. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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Cite this article as: Shaboodien G, Spracklen TF, Kamuli S, Ndibangwi P, Van Niekerk C, Ntusi NAB. Genetics of inherited cardiomyopathies in Africa. Cardiovasc Diagn Ther 2020;10(2):262-278. doi: 10.21037/cdt.2019.10.03