A child in Zambia with unexplained muscle weakness and a child in London from a South Asian family both have the same disease, but only the London child is likely to get a genetic diagnosis. This project tackles a stark inequality: roughly 86% of all genomic studies have been done on people of European ancestry, yet neuromuscular diseases (NMDs) affect 15–20 million people globally. For non-European patients, diagnostic rates are far lower because their genetic architecture is poorly understood. The researchers have already assembled the world’s largest non-European NMD cohort—over 10,000 patients from Africa, India, South America, and Turkey—but 1,500 families remain unsolved. They will now combine these with unsolved UK patients of minority ethnicities and apply advanced techniques: long-read whole genome sequencing to spot large DNA rearrangements, and RNA sequencing to detect downstream effects of mutations. If successful, this work will uncover new genetic causes of NMD that are especially relevant to non-European populations. That could directly improve diagnostic rates in NHS services and globally, enabling better prognosis, complication screening, and access to precision medicines including gene therapies. It is primarily fundamental science—defining disease mechanisms—but with a clear path to reducing health inequality.
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In this project, we aim to address genomic research inequality and resulting health inequality affecting children and adults of non-European ancestries with Neuromuscular Diseases (NMD) in the UK and also globally. We hypothesise that by investigating unsolved diverse populations we will discover novel mechanisms and treatable genetic variants with potential patient benefit. NMD account for ~20% non-infectious neurological diseases, and affect ~15-20 million people globally. NMD can cause muscle wasting and weakness, cardiorespiratory problems, and sensory alteration. Clinical severity ranges from being fatal to causing life-long disability. NMD develop at any age and have few treatments. Most are single gene diseases. There are many benefits to defining the precise genetic cause: 1) improved mechanistic understanding 2) accurate prognosis/genetic counselling 3) gene-specific complication screening/care management, and 4) precision medicine, including genetic therapies. Approximately 50% of European-ancestry NMD remain genetically unsolved and solved rates in NMD patients of non-European ancestry are much lower. This is partly because there is less non-European ancestry NMD cohort genetic data; consequently, non-European NMD genetic architecture is less well understood. Indeed ~86% of all existing genomic studies are on European ancestry. Lack of diverse genetic data is a major knowledge gap and missed opportunity to understand gene function and disease mechanisms. This research inequality is translating into a health inequality; for example, the genetic diagnostic rates in national NHS NMD specialised services we lead are lower for patients of non-European ancestries. We recently assembled the world’s largest non-European NMD cohort (>10,000) in a partnership called ICGNMD with 18 centres across S. Africa, Zambia, India, South America, and Turkey. ICGNMD genetic analysis enabled genetic diagnosis for many families but 1,500 remain unsolved. We propose to (i) combine these international unsolved families with a similar number of unsolved UK research cohort patients of minority ethnicities into a new, unsolved cohort, and (2) undertake further analysis, including new advanced genomic techniques to genetically solve more cases and discover important new insights about the global genetic causes of NMD. First, we will re-analyse our unsolved cohorts to make sure all families that can be solved using existing information are solved. We expect to solve approximately 15% of families by harnessing new clinical information about affected participants and by utilising advances in analysis since we started analysing families in 2020. Next, we will review and discuss the families which remains unsolved with a multidisciplinary global team, and together prioritise a subset for advanced genomic analysis. Then, we will analyse prioritised families using advanced technologies that provide more detailed information about DNA changes in and around genes. One technique called long-read whole genome sequencing (LR-WGS) can identify disease-causing changes affecting larger stretches of DNA, such as sequence expansions, contractions and rearrangements. Another technique called RNA or transcriptome sequencing (RNA-seq) provides data about the effects DNA mutations have at a later stage in the pathway from genes to making proteins that are essential for cell function, and so helps us understand if DNA mutations have downstream effects. At the end of this research we will have defined new genetic causes/mechanisms of NMD that are especially relevant to people of non-European ancestries. We will publish this data and communicate findings to all UK and international patients in our cohorts. We will use/share the data to inform developing new diagnostics and new medicines, including gene therapies.
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