A case for genomic medicine in South

Introduction Neuromuscular disease (NMD) includes a wide spectrum of rare diseases with primary abnormalities in the peripheral nervous system. Progressive muscle weakness is a key feature, as well as impaired ambulation, joint contractures, skeletal deformities, altered sensory perception and respiratory failure. NMDs are predominantly monogenic in origin, and affect at least 20 million children and adults globally, with prevalence rates estimated between 1 and 10 per 100,000 (1). These estimations do not include any of the African populations, which remain significantly understudied (2, 3). Paediatric NMDs are historically associated with a poor prognosis, however, treatment strategies and options have rapidly expanded (4). This is illustrated by recent advances in therapies for Duchenne- and facioscapulohumeral muscular dystrophies (5, 6), and spinal muscular atrophy (7). It is important to identify the population specific genetic origin of NMDs in understudied populations (8), and to apply the knowledge in local new-born screening programs to identify patients who will benefit from specific treatment strategies (9). The South African paediatric patients stem from a unique diversity of African, Asian and Caucasian populations. From data presented here it is evident that NMDs have unique phenotypes and genetic variants in these populations. The lack of data, restricted genetic services, along with socio-economic demands and national health priorities, limit the options and access to treatment for patients with NMDs. Here, we provide perspectives on NMD phenotypes recognised in the South African paediatric populations, clinical and molecular diagnostic challenges, and timely opportunities to address the lack of knowledge and capacity in the form of a multi-centre collaborative genomics medicine platform. Paediatric NMD in the South African populations Diagnostic odyssey Similar to many African populations, South African patients with suspected NMDs, in both the private and public sector, experience a diagnostic odyssey. Only a small number of specialized clinics exist as the portal for disease diagnosis and translational medicine. Moreover, indigenous, or cultural aspects that result in lack of referral and/or referral bias should be acknowledged (8). Further barriers to diagnosis and referral are practitioners lacking training in NMDs. An effective diagnostic approach requires knowledge of phenotypes and genotypes (pathogenic variants and background genetics) in all local populations. Common and population specific NMD phenotypes have been identified, expressed on a genetic background for indigenous African populations that are relatively unreported in genomic databases, as summarised in Table 1 (10–15). Moreover, with Southern Africa being one of the global hot spots for both infectious and non-communicable acquired diseases, national health priorities and subsequent national support structures do not include or promote rare genetic diseases. This is evident in the delay of diagnosis and comprehensive management, including counselling and access to novel therapeutic interventions. Table 1. Known pathogenic variants which are being screened for in patients with neuromuscular and/or mitochondrial or metabolic disease phenotypes in South African populations. Muscular dystrophies Muscular dystrophies include Duchenne and Becker’s muscular dystrophy, congenital muscular dystrophies with and without connective tissue involvement, limb-girdle muscular dystrophies and various other forms named according to the pattern of affected muscle groups. Duchenne muscular dystrophy (DMD) is the most common and severe of the inherited dystrophies, with a worldwide estimated incidence of 1 in 3,500 live male births (18). DMD manifests in boys between 2 and 5 years of age and presents with delayed motor milestones, associated features calf pseudohypertrophy, lumbar lordosis and weakness of the neck flexor muscles (19). A genetic service for DMD and BMD was initiated in Cape Town in 1987 and was the first offered nationally in the state health service (20). Overall minimum prevalence rates of 1/100,000 were calculated, a markedly low prevalence of DMD in the indigenous black population, 1/250,000, contributed to the overall low prevalence (20). Multiple ligase probe amplification (MLPA) was introduced by the National Health Laboratory Service (NHLS) in 2007 which allowed for identification of exonic rearrangements across the gene, not just the hotspots (21) and significantly improved pathogenic variant detection rate from 30 to 45% (19). As an alternate diagnostic aid, the role of cultured skin melanocytes was explored in South Africa (SA, 22). Looking at other African populations, a study from Cameroon identified 17 boys with DMD, diagnosis was delayed into adolescence and significant under-recognition of DMD in the country was hypothesized (23). Patients with LGMD (n = 67) were reported from Mali with onset predominantly in the first decade but the group lacked access to genetic diagnostic closure (24). North African countries are more resourced for access to genetic testing, as illustrated by researchers from Morocco who identified six novel pathogenic variants in the DMD gene following whole dystrophin gene sequencing (25). The perception that novel variants are prevalent in Africa are supported by various case reports (17, 26–29). Genetic testing for other forms of congenital muscular dystrophy is not routinely available through the state service in SA. Awareness of the novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner populations has affected clinical practice through raised awareness and accordingly targeting diagnostic assessments (Table 1, 17). In such cases, an opportunistic muscle biopsy during other essential surgical interventions may be performed and the probable diagnosis may be supported by immunohistochemical stains on light microscopy as well as electron microscopy findings. Spinal muscular atrophy Spinal muscular atrophy (SMA) is the second most common autosomal recessively inherited disorder caused by the homozygous loss of the SMN1 gene (30). It is characterized by degeneration of alpha motor neurons in the spinal cord which results in progressive proximal muscle weakness (30). The incidence of SMA varies between 1 in 6,000 and 1 in 10,000 and carrier frequency between 1 in 40 to 1 in 60 globally (31). In SA, the incidence in the indigenous African populations is estimated to be 1 in 3,574 and in European ancestry populations 1 in 1,945, with carrier frequency of 1 in 50 and 1 in 23 in the Black African and European populations respectively (16). Lower expression of homozygous SMN1 gene deletion is reported in Black South African populations who have phenotypes compatible with SMA. SMN1 deletion heterozygosity was found in at least 70% of these patients (16). A proportion of these patients had additional clinical features inclusive of myopathic facies. The same findings were not replicated in the Western Cape region of SA, where the genotype and phenotype were concordant with international inclusion criteria for SMA (14). Larger national population studies are needed to understand the true prevalence of homozygous SMN1 gene deletions in children with SMA phenotypes across South African ancestries, and to understand the sub-population with additional clinical features. Genetic testing is available through the public and private sectors and for a small proportion carrier testing can be undertaken (Table 1). Newer therapies such as antisense oligonucleotides and gene therapies, whilst available and approved in some high-income countries, are precluded due to the cost in many low- and middle-income countries. Such settings are dependent on compassionate access programs or being part of research studies. Most patients with SMA are therefore left without access to treatment which raises many ethical and moral concerns. In line with this, neonatal screening has not been taken up in SA. Congenital myopathies Congenital myopathies are a group of genetically inherited muscle disorders clinically characterized by hypotonia and weakness (32). Congenital myopathies were traditionally classified
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