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.

Tuberculosis in Myasthenia Gravis patients on immunosuppressive therapy in a high-risk area: Implications for preventative therapy.

Data regarding the risk of tuberculosis (TB) in myasthenia gravis (MG) patients receiving immunosuppressive therapy is limited, and the benefit of TB preventative therapy in these patients is uncertain. We audited observational data collected at an MG clinic in South Africa over a ~ 10-year period, of cases who received immunosuppressive therapy. The total time that the cohort was at risk (patient-years) was used as the denominator to calculate TB incidence after immunosuppressive therapy initiation. Multivariate logistic regression analysis was performed to identify differences between patients who did, and those who did not, develop TB. Of 480 cases, only two received TB preventative therapy when starting immunotherapy. Seventeen of 282 (6%) patients tested, were HIV-infected. With a median follow-up of 3.6 years (interquartile range 1;7.5), 13 (3%) patients (all HIV-uninfected) developed TB (38% within 12 months of starting immunosuppressive therapy). The incidence rate of TB in the study population (≤401/100000 person-years) was not higher than that for the hospital's catchment area during the same period (>500/100000 population). The maximum dose of prescribed prednisone was higher in patients who developed TB compared to those who did not (median: 0.6 mg/kg/day vs 0.4; 0.002); Odds ratio for TB increased 1.26-fold for every 0.1 mg/kg/day increase in maximum dose (p = 0.001). In our TB endemic setting, receiving immunosuppressive therapy was not associated with excess TB in MG patients. Preventative therapy may be considered in those who are at greatest risk of developing TB and receiving high-dose prednisone.