Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Genetic Neuromuscular Disorders and Health Services Access, Utilization, and Needs in Zambia.

BACKGROUND: Medical and rehabilitative advances increasingly transform management of rare genetic neuromuscular diseases (GNMDs) for children in the global north. Lack of information about GNMDs and related health care needs in sub-Saharan Africa threatens to widen pre-existing health disparities. METHODS: This is a cross-sectional study of probands enrolling in a study of GNMDs at the University Teaching Hospital in Lusaka, Zambia, a member of the International Consortium for Genomic Medicine in Neuromuscular Disease. Probands/caregivers were interviewed about utilization of medical, rehabilitative, and other support services by a research assistant. A neuromuscular neurologist and/or physiotherapist examined each case and completed an independent questionnaire regarding health service utilization for each proband. Diagnoses were made on available clinical and electrophysiologic data. Molecular findings were unavailable at the time of this analysis. RESULTS: Among 50 probands, 52% were male with median age 12 (absolute range 2 months to 54 years). Motor neuron diseases (n = 16; 32%), muscle disorders (n = 20; 40%), and inherited polyneuropathies (n = 5; 10%) were most common. Six (15%) cases had insufficient clinical data to classify the GNMDs. Outside of primary care, patient/caregiver-reported access to recommended health services (n = 34; 69%) was challenging. Large disparities in current utilization of health care services versus clinician-recommended services are reported. CONCLUSIONS: Paradigms to improve access to diagnostics and therapeutic interventions are needed for GNMDs in Zambia. Multidisciplinary clinics may improve access and utilization of needed health services. Qualitative and other research focused on improving referrals, access, and quality of available health services are greatly needed.