Genetics of inherited cardiomyopathies in Africa

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.

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. Abbreviations.

Abbreviation	Definition
A2C-AR	Adrenoceptor alpha 2C
ACE	Angiotensin I converting enzyme
ACE2	Angiotensin I converting enzyme 2
ACM	Arrhythmogenic cardiomyopathy
ACTC1	Actin alpha cardiac muscle 1
AGT	Angiotensinogen
AGTR2	Angiotensin II receptor type 2
AIDS	Acquired immune deficiency syndrome
ALA	Alanine
ALU	Arthrobacter luteus
ARG	Arginine
ASN	Asparagine
ASP	Aspartic acid
ATP	Adenosine triphosphate
AG3	BCL2 associated athanogene 3
B1-AR	Adrenoceptor beta 1
B2-AR	Adrenoceptor beta 2
BMHC	Beta myosin heavy chain
CHD	Congenital heart disease
CDH2	Cadherin-2
CMO	Cardiomyopathy
CMR	Cardiovascular magnetic resonance
CSRP3	Cysteine and glycine rich protein 3
CVD	Cardiovascular disease
CYP11B2	Cytochrome P450 family 11 subfamily B member 2
DCM	Dilated cardiomyopathy
DES	Desmin
DMPK	Dystrophia myotonica protein kinas
DSC2	Desmoscollin-2
DSG2	Desmoglein-2
DSP	Desmoplakin
ECG	Electrocardiogram
ECHO	Echocardiogram
EMF	Endomyocardial fibrosis
FHL1	Four and a half LIM domains 1
FLNC	Filamin C
FRMD4A	FERM domain containing 4A
GBE1	1,4-alpha-glucan branching enzyme
GLA	Galactosidase alpha
GLN	Glutamine
GLY	Glycine
HADHB	Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta
HCM	Hypertrophic cardiomyopathy
HF	Heart failure
HFMREF	Heart failure with mildly reduced ejection fraction
HFPEF	Heart failure with preserved ejection fraction
HFREF	Heart failure with reduced ejection fraction
HIS	Histidine
HIV	Human immunodeficiency virus
HO-1	Haem oxygenase 1
ICD	Implantable cardioverter defibrillators
JUP	Junctional-plakophilin
LAMP2	Lysosomal associated membrane protein 2
LAMRIP6	Laminin receptor 1 pseudogene 6
LEU	Leucine
LMICS	Low- and middle-income countries
LMNA	Lamin A/C
LV	Left ventricular
LVEDD	LV end-diastolic diameter
LVEF	Left ventricular ejection fraction
LVH	Left ventricular hypertrophy
LVNC	Left ventricular noncompaction
MET	Methionine
MYBPC3	myosin-binding protein C
MYH7	b-myosin heavy chain
MYL2	Myosin light chain 2
MYL3	Myosin light chain 3
MYPN	Myopalladin
NCD	Noncommunicable disease
NGS	Next generation sequencing
NYHA	New York Heart Association
PKP2	Plakophilin2
PLN	Phospholamban
PPCM	Peripartum cardiomyopathy
PRKAG2	Protein kinase AMP-activated non-catalytic subunit gamma 2
PRO	Proline
RCM	Restrictive cardiomyopathy
RHD	Rheumatic heart disease
RV	Right ventricular
RYR1	Ryanodine receptor 1
SCD	Sudden cardiac death
SDHD	Succinate dehydrogenase complex subunit D
SER	Serine
SNP	Single nucleotide polymorphism
SSA	Sub-Saharan Africa
TAZ	Tafazzin
THR	Threonine
TNNI3	Troponin I3, cardiac type
TNNT2	Troponin T2
TPM1	Tropomyosin 1
TRP	Tryptophan
TTN	Titin
TTR	Transthyretin
US	United States
VT	Ventricular tachycardia
VUS	Variant of unknown significance
WES	Whole exome sequencing

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. Definitions for the inherited cardiomyopathies.

Cardiomyopathy	Definition
DCM	Left or biventricular dilatation and impaired systolic function in the absence of CAD, hypertension, valvular disease or CHD
	◆ International prevalence: 1/250
	® Common signs or symptoms: EF <50%, HF, arrhythmia
	® Age of onset: ~20–50 years
	® Patient management and outcomes: treatment of HF symptoms, heart transplantation, high risk of mortality from HF or SCD
HCM	Unexplained LVH (increased LV wall thickness) in the absence of hypertension or valvular disease
	® International prevalence: 1/500
	® Common signs or symptoms: arrhythmia, chest pain, syncope, HF, SCD or thromboembolism
	® Age of onset: any
	® Patient management and outcomes: risk of HF or SCD, treatment with ICD in high-risk patients to prevent SCD
ACM	Progressive replacement of RV and/or LV myocardium with fibrofatty tissue, often associated with arrhythmia, palpitations or SCD
	® International prevalence: 1/5,000–1/2,000
	® Common signs or symptoms: palpitations, syncope or SCD
	® Age of onset: ~20–40 years
	® Patient management and outcomes: avoidance of strenuous exercise, risk of SCD, treatment with ICD in high-risk patients to prevent SCD
RCM	Restrictive ventricular physiology (increased myocardial stiffness causing reduced ventricular filling), sometimes with reduced systolic and diastolic volumes
	® International prevalence: unknown (rare)
	® Common signs or symptoms: arrhythmia, HF, severe diastolic dysfunction, pulmonary hypertension or conduction defects
	® Age of onset: any
	® Patient management and outcomes: high mortality within first few years often due to HF, SCD or heart block
LVNC	Prominent LV and/or RV trabeculae which may be associated with LV dilatation or impaired systolic function
	® International prevalence: unknown
	® Common signs or symptoms: syncope, arrhythmia, HF, SCD or thromboembolism
	® Age of onset: any age (median age 40–50 years)
	® Patient management and outcomes: treatment of HF symptoms, ICD implantation, risk assessment

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. Studies on the incidence of cardiomyopathy in Africa.

Year	First author	Country	Hospital	Local population size	Study period	Cohort	Disease	Incidence	%	Code-country
1988	Hodes (140)	Ethiopia	Tikur Anbessa Hospital	Unknown	20 months	385 patients	DCM	35/385	9.09	Eastern Africa
1988	Hodes (140)	Ethiopia	Tikur Anbessa Hospital	Unknown	20 months	385 patients	HCM	3/385	0.78	Eastern Africa
1988	Hodes (140)	Ethiopia	Tikur Anbessa Hospital	Unknown	20 months	385 patients	RCM	1/385	0.26	Eastern Africa
1990	Abegaz (75)	Ethiopia	Unknown	Unknown	Jan 1984–June 1988	1,240 echo patients (53 HCM)	HCM	53/1,240	4.27	Eastern Africa
1992	Steenekamp (141)	South Africa	Tshepong Hospital	Unknown	1 year	90 CVD deaths	DCM	17%	17	Southern Africa
1995	Desai (142)	South Africa	King Edward VIII Hospital	Unknown	1986–1989	Unclear	PPCM	1/1,000 births	0.10	Southern Africa
1998	Hakim & Manyemba (143)	Zimbabwe	Harare Central Hospital	Unknown	Not available	1,507 echo patients (310 CMO)	DCM	245/1,507	16.26	Eastern Africa
1998	Hakim & Manyemba (143)	Zimbabwe	Harare Central Hospital	Unknown	Not available	1,507 echo patients (310 CMO)	PPCM	65/1,507	4.31	Eastern Africa
2000	Amoah & Kallen (10)	Ghana	National Cardiothoracic Centre	Unknown	Jan 1992–Dec 1995	572 echo patients (74 CMO)	HCM	9/572	1.57	Western Africa
2000	Amoah & Kallen (10)	Ghana	National Cardiothoracic Centre	Unknown	Jan 1992–Dec 1995	572 echo patients (74 CMO)	DCM	65/572	11.36	Western Africa
2006	Maro (73)	Tanzania	Muhimbili National Hospital	Unknown	June 1998–Oct 2002	6,680 echo patients (134 CMO)	HCM	134/6,680	2.01	Eastern Africa
2007	Heradien (144)	South Africa	Tygerberg Hospital	Unknown	1986–2006	743 CVD (371 HCM)	HCM	371/743	49.90	Southern Africa
2007	Ismail (145)	Uganda	Unknown	Unknown	Not specified	65 HF patients (36 CMO)	DCM	18/65	27.69	Eastern Africa
2007	Ismail (145)	Uganda	Unknown	Unknown	Not specified	65 HF patients (36 CMO)	RCM	18/65	27.69	Eastern Africa
2007	Sani (146)	Nigeria	Unknown	Unknown	Aug 2002–Sept 2004	594 echo patients	DCM	82/594	13.80	Western Africa
2007	Sani (146)	Nigeria	Unknown	Unknown	Aug 2002–Sept 2004	594 echo patients	HCM	28/594	4.71	Western Africa
2008	Ali (147)	Sudan	King Abdulaziz Cardiac Centre	Unknown	Aug 2004–July 2007	4,500 echo patients	LVNC	22/4,500	0.49	Northern Africa
2008	Stewart (148)	South Africa	Chris Hani Baragwanath Hospital (Soweto)	1.1 million	2006	844 HF patients (298 DCM)	DCM	298/844	35.31	Southern Africa
2008	Okoromah (149)	Nigeria	Unknown	Unknown	Jan 2004–Dec 2005	Unclear	DCM	14.3% of paed echo patients	14.30	Western Africa
2008	Soliman & Juma (76)	Malawi	Mzuzu Central Hospital	1.5 million	2001–2005	3,908 CVD patients (726 CMO)	DCM	720/3,908	18.42	Eastern Africa
2008	Soliman & Juma (76)	Malawi	Mzuzu Central Hospital	1.5 million	2001–2005	3,908 CVD patients (726 CMO)	HCM	3/3,908	0.08	Eastern Africa
2008	Soliman & Juma (76)	Malawi	Mzuzu Central Hospital	1.5 million	2001–2005	3,908 CVD patients (726 CMO)	RCM	3/3,908	0.08	Eastern Africa
2008	Ogah (150)	Nigeria	Federal Medical Centre Abeokuta	3.2 million	Sept 2005–Feb 2007	1,441 echo patients	DCM	34/1,441	2.36	Western Africa
2008	Ogah (150)	Nigeria	Federal Medical Centre Abeokuta	3.2 million	Sept 2005–Feb 2007	1,441 echo patients	PPCM	4/1,441 (4/697 females)	0.57 (females)	Western Africa
2008	Ogah (150)	Nigeria	Federal Medical Centre Abeokuta	3.2 million	Sept 2005–Feb 2007	1,441 echo patients	HCM	1/1,441	0.07	Western Africa
2008	Sliwa (151)	South Africa	Chris Hani Baragwanath Hospital (Soweto)	1.1 million	2006	844 HF patients	DCM	296/844	35.07	Southern Africa
2008	Karaye & Sani (152)	Nigeria	Aminu Kano Teaching Hospital	Unknown	6 months	79 HF patients	PPCM	11/35 (females)	31.43	Western Africa
2008	Karaye & Sani (152)	Nigeria	Aminu Kano Teaching Hospital	Unknown	6 months	79 HF patients	DCM	8/79	10.13	Western Africa
2009	Mbakwem (153)	Nigeria	Lagos University Teaching Hospital	Unknown	1998–2000	712 echo patients	HCM	14/712	1.97	Western Africa
2009	Onwuchekwa & Asekomeh (154)	Nigeria	University of Port-Harcourt Teaching Hospital	Unknown	Jan 2001–Dec 2005	423 HF patients (32 CMO)	DCM	31/423	7.33	Western Africa
2009	Onwuchekwa & Asekomeh (154)	Nigeria	University of Port-Harcourt Teaching Hospital	Unknown	Jan 2001–Dec 2005	423 HF patients (32 CMO)	RCM	1/423	0.24	Western Africa
2009	Adebayo (155)	Nigeria	University College Hospital Ibadan	>3 million	Not stated	177 HF patients	DCM	24/177	13.56	Western Africa
2010	Habte (156)	Ethiopia	Jimma University Specialized Hospital	200,000	2003–2008	781 CVD patients (158 DCM)	DCM	158/781	20.23	Eastern Africa
2010	Stewart (157)	South Africa	Chris Hani Baragwanath Hospital (Soweto)	1.1 million	2006–2008	5,328 suspected CVD cases	DCM	502/5,328	9.42	Southern Africa
2010	Ntep-Gweth (158)	Cameroon	Chris Hani Baragwanath Hospital (Soweto)	1.1 million	June 2006–June 2007	172 atrial fibrillation patients	DCM	27/172	15.70	Southern Africa
2011	Ogeng’o (159)	Kenya	Not applicable (not a hospital study)	Unknown	Dec 2005–Nov 2009	134 CV deaths	Unspecified CMOs	23/134	17.16	Eastern Africa
2012	Peters (160)	South Africa	Chris Hani Baragwanath Hospital (Soweto)	Unknown	Jul 2009–Dec 2010	780 echo patients (54 LVNC)	LVNC	54/780	6.92	Southern Africa
2012	James (95)	Nigeria	University of Port-Harcourt teaching hospital	Unknown	May 2009Apr 2010	234 echo patients (18 CMO)	DCM	13/234	5.56	Western Africa
2012	James (95)	Nigeria	University of Port-Harcourt teaching hospital	Unknown	May 2009–Apr 2010	234 echo patients (18 CMO)	HCM	4/234	1.71	Western Africa
2012	James (95)	Nigeria	University of Port-Harcourt teaching hospital	Unknown	May 2009–Apr 2010	234 echo patients (18 CMO)	ACM	1/234	0.43	Western Africa
2012	Stewart (161)	South Africa	Mandela Sisulu and Pimville primary care clinics (Soweto)	Unknown	Jun 2009–Dec 2009	1,311 patients (3 DCM)	DCM	3/1,311	0.23	Southern Africa
2012	Goeh Akue (162)	Togo	Tokoin Teaching Hospital	Unknown	Jan 2007–Feb 2009	1,152 pregnancies (9 CMO)	PPCM	9/1,152 (1:128)	0.78	Western Africa
2012	Schwartz (163)	Botswana	Princess Marina Hospital	199,000	Aug 2007–Dec 2008	179 cardiomegaly patients	DCM	13/179	7.26	Southern Africa
2012	Schwartz (163)	Botswana	Princess Marina Hospital	199,000	Aug 2007–Dec 2008	179 cardiomegaly patients	PPCM	19/179 (19/103 females)	18.45 (female)	Southern Africa
2012	Tomaszewski (164)	Nigeria	Unknown	Unknown	2002–2011	170 cardiomegaly patients	DCM	37/170	21.76	Western Africa
2012	Jamaledeen (165)	Sudan	Unknown	Unknown	Apr 2010–July 2010	67 HF patients	DCM	7/67	10.45	Northern Africa
2013	Schmied (166)	Gabon	Not applicable (not a hospital study)	Unknown	Not indicated	210 football players (1 HCM)	HCM	1/210	0.48	Central Africa
2013	Massoure (167)	Djibouti	Military Hospital Bouffard	Unknown	Jan 2009–Dec 2010	156 paed echo patients (5 paed DCM)	DCM	5/156	3.21	Eastern Africa
2013	Kwan (168)	Rwanda	Two hospitals in Kirehe and Southern Kayonza	350,000	Nov 2006–Mar 2011	192 HF echo patients	DCM	79/192	41.15	Eastern Africa
2013	Jingi (169)	Cameroon	Centre Medical de la Trinité	1.8 million	Jul 2008–Oct 2010	1,252 echo patients (382 CMO)	DCM	300/1,252	23.96	Central Africa
2013	Jingi (169)	Cameroon	Centre Medical de la Trinité	1.8 million	Jul 2008–Oct 2010	1,252 echo patients (382 CMO)	HCM	72/1,252	5.75	Central Africa
2013	Jingi (169)	Cameroon	Centre Medical de la Trinité	1.8 million	Jul 2008–Oct 2010	1,252 echo patients (382 CMO)	RCM	10/1,252	0.80	Central Africa
2013	Ogeng’o (170)	Kenya	Kenyatta National Hospital	Unknown	Jan 2006–Dec 2010	158 paed HF patients	Unspecified CMOs	12/158	7.59	Eastern Africa
2013	Kennedy & Miller (171)	Malawi	Queen Elizabeth Central Hospital	1 million	Jan 2009–Feb 2011	250 paed echo patients (38 paed CMO)	DCM	34/250	13.60	Eastern Africa
2013	Kennedy & Miller (171)	Malawi	Queen Elizabeth Central Hospital	1 million	Jan 2009–Feb 2011	250 paed echo patients (38 paed CMO)	HCM	1/250	0.40	Eastern Africa
2013	Kennedy & Miller (171)	Malawi	Queen Elizabeth Central Hospital	1 million	Jan 2009–Feb 2011	250 paed echo patients (38 paed CMO)	LVNC	3/250	1.20	Eastern Africa
2013	Adebayo (172)	Nigeria	Obafemi Awolowo University Teaching Hospitals Complex	Unknown	2002–2010	2,501 echo patients	Unspecified CMOs	42/2,501	1.68	Western Africa
2013	Taha (173)	Egypt	El-Minia University Hospital	Unknown	Jan 2009–Dec 2009	121 pregnant patients with structural heart disease	PPCM	3/121	2.48	Northern Africa
2013	Massoure (174)	Djibouti	Military Hospital Bouffard	Unknown	Aug 2008–Dec 2010	1,688 HF hospitalisations	DCM	118/1,688	6.99	Eastern Africa
2013	Ansa (175)	Nigeria	University of Calabar Teaching Hospital	Unknown	Unclear (1 year)	321 echo patients	DCM	31/321	9.66	Western Africa
2013	Bode-Thomas (176)	Nigeria	Jos University Teaching Hospital	Unknown	Unclear (10 years)	175 paed acquired heart disease cases	DCM	33/175	18.86	Western Africa
2014	Oyedeji (177)	Nigeria	CNL Hospital	Unknown	May 2011–Apr 2013	168 echo patients	HCM	2/168	1.19	Western Africa
2014	Ogah (178)	Nigeria	Unknown	Unknown	Jan 2009–Dec 2010	285 HF patients (30 CMO)	DCM	24/285	8.42	Western Africa
2014	Ogah (178)	Nigeria	Unknown	Unknown	Jan 2009–Dec 2010	285 HF patients (30 CMO)	PPCM	6/285 (6/135 women)	2.1 (4.4 women)	Western Africa
2014	Ogah (179)	Nigeria	Federal Medical Centre, Idi-Aba, and Abeokuta	3.2 million	Jan 2009–Dec 2010	452 HF patients (40 CMO)	DCM	34/452	7.52	Western Africa
2014	Ogah (179)	Nigeria	Federal Medical Centre, Idi-Aba, and Abeokuta	3.2 million	Jan 2009–Dec 2010	452 HF patients (40 CMO)	PPCM	6/452 (6/204 women)	1.33 (2.94 women)	Western Africa
2014	Yameogo (180)	Burkina Faso	Yalgado Ouedraogo University Hospital	Unknown	Jan 2011–Dec 2012	128 CV deaths (43 CMO)	DCM	35/128	27.34	Western Africa
2014	Yameogo (180)	Burkina Faso	Yalgado Ouedraogo University Hospital	Unknown	Jan 2009–Dec 2010	128 CV deaths (43 CMO)	PPCM	8/128	6.25	Western Africa
2014	Abdissa (181)	Ethiopia	Tikur Anbessa Specialized Tertiary Referral Hospital	Unknown	Jan 2001–Dec 2012	3,282 CVD patients	Unspecified CMOs	62/3,282	1.89	Eastern Africa
2014	Makubi (182)	Tanzania	Muhimbili National Hospital	45 million	Feb 2012–Aug 2013	427 HF patients (114 CMO)	DCM	96/427	22.48	Eastern Africa
2014	Makubi (182)	Tanzania	Muhimbili National Hospital	45 million	Feb 2012–Aug 2013	427 HF patients (114 CMO)	PPCM	18/427	4.22	Eastern Africa
2014	Otaigbe (183)	Nigeria	University of Port Harcourt Teaching Hospital and Paediatric Care Hospital	Unknown	Apr 2009–Mar 2013	356 paed echo patients	DCM	2/356	0.56	Western Africa
014	Otaigbe (183)	Nigeria	University of Port Harcourt Teaching Hospital and Paediatric Care Hospital	Unknown	Apr 2009–Mar 2013	356 paed echo patients	HCM	2/356	0.56	Western Africa
2014	Pelemo (184)	Nigeria	Obafemi Awolowo University Teaching Hospitals Complex	1.5 million	Jan 2001–Dec 2010	159 sudden unexpected natural deaths	DCM	3/159	1.89	Western Africa
2014	Pelemo (184)	Nigeria	Obafemi Awolowo University Teaching Hospitals Complex	1.5 million	Jan 2001–Dec 2010	159 sudden unexpected natural deaths	HCM	2/159	1.26	Western Africa
2014	Pio (185)	Togo	CHU Sylvanus Olympio	Unknown	Jan 2009–Nov 2012	376 hospitalised patients (echo)	PPCM	58/376	15.43	Western Africa
2014	Pio (185)	Togo	CHU Sylvanus Olympio	Unknown	Jan 2009–Nov 2012	376 hospitalised patients (echo)	DCM	22/376	5.85	Western Africa
2014	Behairy (94)	Egypt	Kasr El Aini Hospital	Unknown	May 2012–Jun 2013	54 suspected CMO cases	DCM	7/54	12.96	Northern Africa
2014	Behairy (94)	Egypt	Kasr El Aini Hospital	Unknown	May 2012–Jun 2013	54 suspected CMO cases	HCM	7/54	12.96	Northern Africa
2014	Behairy (94)	Egypt	Kasr El Aini Hospital	Unknown	May 2012–Jun 2013	54 suspected CMO cases	RCM	6/54	11.11	Northern Africa
2014	Behairy (94)	Egypt	Kasr El Aini Hospital	Unknown	May 2012–Jun 2013	54 suspected CMO cases	ACM	3/54	5.56	Northern Africa
2014	Behairy (94)	Egypt	Kasr El Aini Hospital	Unknown	May 2012–Jun 2013	54 suspected CMO cases	LVNC	3/54	5.56	Northern Africa
2015	Nkoke (186)	Cameroon	Yaoundé General Hospital	2 million	Aug 2003–Dec 2013	9,777 paed echo patients (158 acquired heart disease)	DCM	25/158 acquired heart diseases	15.82	Central Africa
2015	Ekpe (187)	Nigeria	University of Uyo Teaching Hospital	Unknown	1 year	163 echo patients	Unspecified CMOs	21/163	12.88	Western Africa
2015	O’Dwyer (188)	South Africa	Groote Schuur Hospital	>38,000	2 years	44 hypertensive pregnancy disease cases	PPCM	1/44	2.27	Southern Africa
2015	Rulisa (189)	Rwanda	University Teaching Hospital of Kigali	Unknown	Oct 2011–Oct 2012	192 ‘near miss’ maternal patients	PPCM	7/192	3.65	Eastern Africa
2015	Adebayo (190)	Nigeria	Obafemi Awolowo University Teaching Hospitals Complex	Unknown	2 years	310 ECG patients	DCM	7/310	2.26	Western Africa
2015	Bouqata (191)	Morrocco	Mohammed V Military Hospital	Unknown	Jan 2008–Sept 2012	220 HF patients	DCM	97/220	44.09	Northern Africa
2015	Bouqata (191)	Morocco	Mohammed V Military Hospital	Unknown	Jan 2008–Sept 2012	220 HF patients	LVNC	8/220	3.64	Northern Africa
2016	Tougouma (192)	Burkina Faso	University Hospital Souro Sanou	Unknown	Jan 2013–Dec 2014	184 paed echo patients (9 paed DCM)	DCM	9/184	4.89	Western Africa
2016	Bloomfield (193)	Kenya	Moi Teaching and Referral Hospital	13 million	Jun 2010–Dec 2012	118 HF cases (24 CMO)	DCM	23/118	19.49	Eastern Africa
2016	Bloomfield (193)	Kenya	Moi Teaching and Referral Hospital	13 million	Jun 2010–Dec 2012	118 HF cases (24 CMO)	HCM	1/118	0.85	Eastern Africa
2016	Soma-Pillay (194)	South Africa	Unknown	Unknown	2011–2013 (3 years)	118 maternal deaths	PPCM	40/118	33.90	Southern Africa
2016	Abebe (195)	Ethiopia	Gondar University Referral Hospital	Unknown	Dec 2010–Dec 2015	311 HF patients	DCM	39/311	12.54	Eastern Africa
2016	Bakeet (196)	Egypt	Sohag University Hospital	Unknown	Mar 2014–Feb2015	50 paed CMO patients	DCM	38/50	76.00	Northern Africa
2016	Bakeet (196)	Egypt	Sohag University Hospital	Unknown	Mar 2014–Feb 2015	50 paed CMO patients	HCM	12/50	24.00	Northern Africa
2017	Tessema (197)	Ethiopia	Unknown	Unknown	1990 – 2013	15,234 maternal deaths (3,915 PPCM)	PPCM	25.7% due to PPCM	25.70	Eastern Africa
2017	Animasahun (198)	Nigeria	Lagos University Teaching Hospital	Unknown	Jan 2007–Jun 2016	125 paed CVD patients (36 paed CMO)	DCM	26/125	20.80	Western Africa
2017	Animasahun (198)	Nigeria	Lagos University Teaching Hospital	Unknown	Jan 2007–Jun 2016	125 paed CVD patients (36 paed CMO)	HCM	5/125	4.00	Western Africa
2017	Animasahun (198)	Nigeria	Lagos University Teaching Hospital	Unknown	Jan 2007–Jun 2016	125 paed CVD patients (36 paed CMO)	RCM	5/125	4.00	Western Africa
2017	Nkoke (199)	Cameroon	Buea Regional Hospital	130,000	Jun 2016–Apr 2017	529 echo patients (239 CMO)	DCM	42/529	7.94	Central Africa
2017	Nkoke (199)	Cameroon	Buea Regional Hospital	130,000	Jun 2016–Apr 2017	529 echo patients (239 CMO)	PPCM	2/529	0.38	Central Africa
2017	Nkoke (199)	Cameroon	Buea Regional Hospital	130,000	Jun 2016–Apr 2017	529 echo patients (239 CMO)	HCM	2/529	0.38	Central Africa
2017	Yadeta (77)	Ethiopia	Tikur Anbessa Specialised Hospital, Ayder Hospital, Gondar University Hospital, Jimma University Hospital, Saint Paul Medical College Hospital, and Hawassa University Hospital	Unknown	1 Jan–30 Jun 2015	6,275 CVD patients	DCM	477/6,275	7.60	Eastern Africa
2017	Yadeta (77)	Ethiopia	Tikur Anbessa Specialised Hospital, Ayder Hospital, Gondar University Hospital, Jimma University Hospital, Saint Paul Medical College Hospital, and Hawassa University Hospital	Unknown	1 Jan–30 Jun 2015	6,275 CVD patients	HCM	21/6,275	0.33	Eastern Africa
2017	Yadeta (77)	Ethiopia	Tikur Anbessa Specialised Hospital, Ayder Hospital, Gondar University Hospital, Jimma University Hospital, Saint Paul Medical College Hospital, and Hawassa University Hospital	Unknown	1 Jan–30 Jun 2015	6,275 CVD patients	RCM	7/6,275	0.11	Eastern Africa
2017	Yameogo (200)	Burkina Faso	University Hospital Yalgado Ouedraogo	Unknown	1 Jan–30 Jun 2014	230 hospitalisations	DCM	75/230	32.61	Western Africa
2017	Mwita (201)	Botswana	Princess Marina Hospital	>230,000	Feb 2014–Feb 2015	193 HF patients	DCM	38/193	19.69	Southern Africa
2017	Aw (202)	Senegal	Aristide Le Dantec Teaching Hospital	Unknown	Mar–Jun 2013	326 hospitalisations	PPCM	19/326	5.83	Western Africa
2018	Raphael (96)	Tanzania	St Francis Referral Hospital	1 million	Dec 2015–Oct 2017	874 echo patients (118 CMO and 12 paed CMO)	DCM	52/815 (adult); 9/59 (paediatric)	6.38 (adult); 15.25 (paed)	Eastern Africa
2018	Raphael (96)	Tanzania	St Francis Referral Hospital	1 million	Dec 2015–Oct 2017	874 echo patients (118 CMO and 12 paed CMO)	PPCM	56/815 (adult)	6.87	Eastern Africa
2018	Raphael (96)	Tanzania	St Francis Referral Hospital	1 million	Dec 2015–Oct 2017	874 echo patients (118 CMO and 12 paed CMO)	HCM	8/815 (adult); 2/59 (paediatric)	0.98 (adult); 3.39 (paed)	Eastern Africa
2018	Raphael (96)	Tanzania	St Francis Referral Hospital	1 million	Dec 2015–Oct 2017	874 echo patients (118 CMO and 12 paed CMO)	ACM	2/815 (adult); 1/59 (paediatric)	0.25 (adult); 1.69 (paed)	Eastern Africa
2018	Malamba-Lez (203)	DR Congo	Unknown	Unknown	Nov 2014–Sept 2016	231 HF patients (129 CMO)	DCM	110/231	47.62	Central Africa
2018	Malamba-Lez (203)	DR Congo	Unknown	Unknown	Nov 2014–Sept 2016	231 HF patients (129 CMO)	PPCM	19/231	8.23	Central Africa
2019	Ikama (204)	DR Congo	Unknown	Unknown	Jan 2011–Dec 2013	1,125 hypertension patients	HCM	556/1,125	49.42	Central Africa
2019	Ikama (204)	DR Congo	Unknown	Unknown	Jan 2011–Dec 2013	1125 hypertension patients	DCM	77/1125	6.84	Central Africa

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. Incidence of cardiomyopathy in the five regions in Africa (Northern, Southern, Central, Eastern and Western).

Country	Adult incidence (%)	PAED incidence (%)
DCM: 52 studies†	Range (0.2–76.0%)	Range (3.21–20.8)
21 studies in Western Africa++	0.56–32.6	4.89–20.8
14 studies in Eastern Africa^	1.3–41.0	3.21–15.3
5 studies in Central Africa#	7.0–47.6	15.82
8 studies in Southern Africa@	0.2–35.3	Unknown
4 studies in Northern Africa*	13.0–76.0	–
HCM: 24 studies†	Range (0.08–49.9)	Range (0.4–4.0)
9 studies in Western Africa++	1.2–2.0	4
8 studies in Eastern Africa^	0.08–4.3	0.4–3.4
4 studies in Central Africa#	0.5–45.0	–
2 studies in Northern Africa*	13.0–24.0	–
1 study in Southern Africa@	49.9	–
RCM: 8 studies†	Range (0.08–27.7%)
4 studies in Eastern Africa^	0.8–27.7	–
2 studies in Western Africa++	0.24	4
1 study in Central Africa#	0.8	–
1 study in Northern Africa*	2.5	–
LVNC: 5 studies†	Range (0.5–6.9%)
3 studies in Northern Africa*	0.5–5.6	–
1 study in Eastern Africa^	–	1.2
1 study in Southern Africa@	6.9	–
ACM:3 studies†	Range (0.3–5.6%)
1 study in Eastern Africa^	0.3	1.7
1 study in Western Africa++	0.4	–
1 study in Northern Africa*	5.6	–

*, Northern Africa (7 countries): the northernmost part of the continent are Algeria, Egypt, Libya, Morocco, Sudan, Tunisia, Western Sahara; ^#, Central Africa Central or Middle African countries (9 countries): Angola, Cameroon, Central African Republic, Chad, Congo Republic—Brazzaville, Democratic Republic of Congo, Equatorial Guinea, Gabon, and São Tomé & Princip; ^@, Southern Africa countries (5 countries): Botswana, Lesotho, Namibia, South Africa, and Swaziland; ^{^}, East Africa (19 countries): Burundi, Comoros, Djibouti, Ethiopia, Eritrea, Kenya, Madagascar, Malawi, Mauritius, Mozambique, Réunion, Rwanda, Seychelles, Somalia, Somaliland, Tanzania, Uganda, Zambia, and Zimbabwe; ⁺⁺, Western Africa (17 countries): Benin, Burkina Faso, Cape Verde, Côte D’Ivoire, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Mauritania, Niger, Nigeria, Saint Helena, Senegal, Sierra Leone, and Togo. ^†, Studies found in Table S2.

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. Genetic studies of inherited cardiomyopathies in Africa.

Year	First author (ref)	Cohort size	Techniques	Study type	Gene(s)	Variant/s	Country
Dilated cardiomyopathy
1999	Candy (37)	171	Genotyping	SNP assoc. (LVH) (+ve)	ACE	287bp alu repeat (intron16)	South Africa
2002	Tiago (38)	107	Candidate gene	SNP assoc. (impr. LVEF) (+ve)	ACE†, AGT‡, CYP11B2§	Insertion/deletion†, c.704T > C‡ and c.344C > T§	South Africa
2007	Badenhorst (39)	394	Genotyping	SNP assoc. (LVEF&LVEDD)	β2-AR	p.R16G and p.Q27E	South Africa
2008	Du Preez (40)	37	Genotyping	SNP assoc. (risk HF)	α2C-AR	Del322-325	South Africa
2008	Woodiwiss (41)	132	Genotyping	SNP assoc. (HF risk)	α2C-AR¶ and β1-AR&	p.G389R¶ and Del322-325&	South Africa
2010	Mahjoub (42)	76	Genotyping	SNP assoc. (risk of DCM) (+ve)	ACE	DD vs. ID genotype	Tunisian
2015	Sayed (43)	60	Genotyping	PCR	HO-1	GT (n) repeats	Egyptians
2016	Fish (44)	315	Candidate gene	Gene screen	PLN	p.R9C	South Africa
2018	Adadi (32)	One family	NGS	Targeted resequencing	LMNA (50 genes)	p.R541C	Morocco
Hypertrophic cardiomyopathy
2009	Heradien (45)	143	Genotyping	SNP assoc. (BP) (+ve)	TNNT2, MYH7	p.R92W	South Africa
1993	Moolman (46)	5	Candidate gene	Gene screen	βMHC	p.R403	South Africa
1995	Moolman (47)	32	Candidate gene	Gene screen	βMHC	p.A797T	South Africa
1995	Posen (48)	2 large pedigrees	Candidate gene	Gene screen	βMHC	p.R403Trp and p.R249Q	South Africa
1997	Tesson (49)	114	Genotyping	SNP assoc. (LVH) (+ve)	ACE	p.R403	South Africa
1997	Moolman (50)	48	Candidate gene	Gene screen	TNNT2	p.R92W	South Africa
1998	Moolman-Smook (51)	4	Candidate gene	Gene screen	MYBPC3	p.R654H	South Africa
1999	Moolman-Smook (52)	40	Candidate gene	Gene screen	βMHC, MYBPC	p.Q499K in βMHC and p.V896M and 756 in MYBPC	South Africa
2001	Andersen (53)	68	Candidate gene	Gene screen	MYL2 and MYL3	None found	South Africa
2002	Blair (54)	82	Candidate gene	Gene screen	MYH7	p.A1379R and p.S1776G	South Africa
2000	Moolman-Smook (55)	66	Genotyping	SNP assoc. (prognosis) (+ve)	MYH7	c.797A > T	South Africa
2008	van der Merwe (56)	227	Genotyping	SNP assoc. (LVH) (+ve)	ACE2	rs1978124, rs2285666 or rs4646179, and rs879922	South Africa
2011	Carstens (57)	353	Genotyping	SNP assoc. (LVH) (+ve)	AGTR2	+1645G > A	South Africa
2012	Kassem (58)	192	Candidate gene	Gene screen	MYBPC3, MYH7, and TNNT2	40% mutation rate in cohort	Egypt
2016	Jafaar (59)	45	Targeted	NGS	MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, FLNC	27% cases mutation positive, predominantly in MYBPC3 and MYH7 as well as MYL3	Tunisia
2016	Mouton (60)	388	Genotyping	7 SNPs as modifiers (+ve)	MYBPH	c.1093+449T > C (rs2250509)	South Africa
2016	Ntusi (61)	43	NGS	Targeted resequencing	MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, PLN, CSRP3, FHL1, PRKAG2, GLA, LMNA, LAMP2	MYH7 (p.R204H); MYH7 (p.T761N); MYH7 31 (p.R1420W); MYBPC3 (p.E334K); MYH7 (p.R723C); MYH7 (p.R249Q); MYBPC3 (p.E258K); MYBPC3 (p.R177H); MYH7 (p.R453C); MYBPC3 (p.G416S)	South Africa
2017	Lahrouchi (62)	One family	NGS	WES	SLC22A5	p.Y396*	Morocco
Arrhythmogenic cardiomyopathy
2006	Matolweni (63)	13	Linkage	Gene screen	ITG8, FRMD4A, LAMRIP6	None found	South Africa
2009	Watkins (64)	50	Candidate gene	Gene screen	PKP2	p.IVS2146-1G-C, p.A733fsX740, p.Q378X, p.R388W, p.G489R, p.S837fs, p.L847P	South Africa
2017	Choung (65)	1	NGS	Targeted resequencing	MYBPC3	p.E1179K	East Africa
2017	Mayosi (66)	2	NGS	WES	CDH2	p.Q229P and p.D407N	South Africa
Restrictive cardiomyopathy
2015	Mouton (67)	113	Candidate gene	Gene screen	TNNI3	p.L144H, de novo p.R170Q	South Africa

^†, ACE insertion/deletion; ^‡, AGT c.344C>T; ^§, CYP11B2 c.344C>T; ^¶, α2C-AR p.G389R; ^&, β1-AR Del322-325; *, SLC22A5 p.Y396.

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.

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/.