Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†.

BACKGROUND: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries. METHODS: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway. RESULTS: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents. CONCLUSIONS: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Modern genomic techniques in the identification of genetic causes of cardiomyopathy.

Over the past three decades numerous disease-causing genes have been linked to the pathogenesis of heritable cardiomyopathies, but many causal genes are yet to be identified. Next-generation sequencing (NGS) platforms have revolutionised clinical testing capacity in familial cardiomyopathy. In this review, we summarise how NGS technologies have advanced our understanding of genetic non-syndromic cardiomyopathy over the last decade. First, 26 putative new disease-causing genes have been identified to date, mostly from whole-exome sequencing, and some of which (FLNC, MTO1, HCN4) have had a considerable clinical impact and are now included in routine diagnostic gene panels. Second, we consider challenges in variant interpretation and the importance of large-scale NGS population control cohorts for this purpose. Third, an emerging role of common variation in some forms of genetic cardiomyopathy is being elucidated through recent studies which have illustrated an additive effect of numerous polymorphic loci on cardiac parameters; this may explain phenotypic variability and low rates of genetic diagnosis from sequencing studies. Finally, we discuss the clinical utility of genetic testing in cardiomyopathy in Western settings, where NGS panel testing of core disease genes is currently recommended with possible implications for patient management. Given the findings of recent studies, whole-exome or whole-genome sequencing should be considered in patients of non-European ancestry with clearly familial disease, or severe paediatric disease, when no result is obtained on panel sequencing. The clinical utility of polygenic risk assessment needs to be investigated further in patients with unexplained dilated cardiomyopathy and hypertrophic cardiomyopathy in whom a pathogenic variant is not identified.

Genetic counseling experiences at the University of Cape Town during COVID-19.

Soon after the first COVID-19 case was reported in December 2019 in Wuhan, China, South Africa announced a national lockdown in an attempt to curb the spread of the disease. Under national lockdown, businesses were closed, learning institutions moved to emergency remote teaching (ERT), and hospitals reduced their patient loads. De-escalation of clinical services at Groote Schuur and Red Cross War Memorial Children's Hospitals affected Genetic Counseling Services and resulted in a decrease in in-person and an increase in telecounseling sessions. ERT, offered by the University of Cape Town, affected the teaching of Genetic Counseling students, and other methods of training had to be found to compensate for the lack of patient contact. In this paper, we present our Genetic Counseling team's experiences of learning and clinical services during the COVID-19 pandemic in South Africa. The team met online as a group in November 2020 to discuss their experiences. The discussion was recorded and transcribed, and topics that arose during the discussion were identified. The pandemic and the accompanying lock down, which forced trainees to move back home, resulted in great uncertainty. The trainees found ERT on an online platform, including simulated cases, very helpful, but they lost the confidence to work with real patients. Telecounseling became the predominant form of service delivery and was experienced as positive when video sessions were possible. The telephone service for advanced maternal age counseling was problematic due to unreliable networks. The biggest loss for the GCs was the feeling of disconnection from peers, supervisors, and patients. The experiences highlighted positive and negative aspects as well as specific challenges faced in South Africa. Lessons learnt from the COVID-19 pandemic will be used in future to improve training of GCs and to enhance service delivery.

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.

Importance: Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective: To identify common genetic loci associated with RHD susceptibility in Black African individuals. Design, Setting, and Participants: This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021. Main Outcomes and Measures: Genetic associations with RHD. Results: This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals. Conclusions and Relevance: This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.

A qualitative study exploring caregivers' experiences, perspectives, and expectations for precision medicine in epilepsy in South Africa.

PURPOSE: Successful implementation of innovative Precision Medicine initiatives in the management of children with complex epilepsy is largely dependent on the caregivers' engagement with the technology as well as its accessibility and acceptability. We investigated the feasibility of implementing these initiatives in the South African setting by gathering information on the caregivers' experiences, perspectives, and expectations for Precision Management of Epilepsy (PME) initiatives. METHODS: We purposively recruited 12 participants from a cohort of 40 caregivers of children with complex epilepsy recruited for a PME study attending Red Cross War Memorial Children's Hospital (RCWMCH) in Cape Town, South Africa. Face-to-face semi-structured interviews were conducted using a pragmatic qualitative approach and themes were extracted using a thematic framework approach. RESULTS: All participants had ideas about the cause of epilepsy, but many did not think that epilepsy is a medical condition. There were several difficulties in adhering to medical treatment which was sometimes combined with traditional remedies and practices. Understanding of Precision Medicine in the context of research was limited and although participants were unclear about benefits, most were optimistic about the future. mHealth devices introduced new feelings and challenges for many participants. The four themes which emerged were: (1) Cause of epilepsy: uncertainty and conflicting views; (2) Need for healing; (3) PME mHealth devices; and (4) Feasibility of implementation of PME initiatives. CONCLUSION: For Precision Medicine to be widely accepted and beneficial, how people understand the cause of epilepsy, difficulties in adherence to treatment, and personal experiences need to be addressed.

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

BACKGROUND: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans. METHOD: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study. CONCLUSION: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.

Psychiatric genetic counseling: A mapping exercise.

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward.

Perceptions of parents of children with hearing loss of genetic origin in South Africa.

More than 80% of people with hearing loss (HL) live in low- and middle-income countries. Up to 90% of deaf children are born to hearing parents, leading to novel parenting, communication, educational, and psychosocial experiences. Half of congenital pre-lingual HL is genetic, with a relatively high recurrence risk that may lead to specific challenges for parents of affected children. Currently, little is known of genes implicated and causative mutations for most populations who have HL in Sub-Saharan Africa, as well as genetic counseling services needs for this population. Therefore, this study aimed to explore parents' perceptions and understanding of the genetic etiology of their child's HL, in order to inform policies and services. In-depth qualitative interviews were conducted with 11 parents of children who have non-syndromic HL of putative genetic origin. Data were analyzed through the framework approach. Three salient themes emerged, namely comprehension and understanding of the cause, in which most parents were unable to identify the potential hereditary cause of their child's HL; responsibility and blame; and their perception of genetic counseling and testing. Most of the participants had positive attitudes towards genetic testing, describing that it may provide answers and that the information gained would be helpful for the future. The data could assist in understanding the challenges faced by parents, in the absence of genetic testing, emphasizing the need for accurate genetic testing to support counseling services to parents of children with HL in an African Setting.

Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families. METHODS AND RESULTS: Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype-phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (CDH2) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis. CONCLUSIONS: These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.

Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia.

Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene. Affected individuals manifest severe congenital anomalies and significant pigmentary changes and are additionally at risk for early onset leukemia and certain solid organ malignancies, including Wilms tumors and brain tumors. Parents of affected individuals are obligate carriers for heterozygous BRCA2 mutations and are thus potentially at risk for adult onset cancers which fall within the hereditary breast and ovarian cancer spectrum. We present two cases of black South African patients with FA diagnosed with biallelic BRCA2 mutations and discuss the phenotypic consequences and implications for them and their families. Recognition of this severe end of the phenotypic spectrum of FA is critical in allowing for confirmation of the diagnosis as well as cascade screening and appropriate care of family members.