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

Area of Science:

• Genomics and Bioinformatics
• Neurology and Genetic Medicine
• Global Health Equity

Background:

• Neuromuscular diseases (NMDs) impact millions globally, with diagnosis and treatment heavily reliant on DNA-based methods.
• Access to advanced genetic diagnostics and therapies is limited in low- and middle-income countries (LMICs).
• Existing genetic databases are predominantly European, creating significant data inequality and hindering diagnosis in diverse populations.

Purpose of the Study:

• To establish a transcontinental, cloud-based partnership to build diverse, deeply-phenotyped, and genetically characterized NMD cohorts.
• To improve the understanding of NMD genetic architecture across diverse ancestries.
• To advance genetic diagnosis and clinical management for NMD patients globally, particularly in under-represented regions.

Main Methods:

• Formation of a collaborative network connecting 18 centers across Brazil, India, South Africa, Turkey, Zambia, the Netherlands, and the UK.
• Development and implementation of a cloud-based data solution for cohort management and analysis.
• Training of international neurology fellows in clinical genomic data interpretation, followed by collaborative analysis of single gene and whole exome data via a bespoke bioinformatics pipeline.

Main Results:

• Recruitment of 6001 participants within 43 months, creating a large dataset from under-represented populations.
• Achieved a diagnostic yield of approximately 56% ('solved' or 'possibly solved') for probands overall, with higher rates for common NMD categories (∼59% solved, ∼13% possibly solved).
• Identified nearly 29% novel disease-causing variants, significantly expanding knowledge of pathogenic variants in diverse populations.

Conclusions:

• A remote, transcontinental partnership effectively assessed the genetic architecture of NMDs across diverse populations.
• The initiative successfully supported DNA-based diagnosis, enabling genetic counseling, improved care pathways, and eligibility for gene-specific trials.
• This model of virtual collaboration can be replicated in other global genomic neurological practices to reduce data inequality and benefit patients worldwide.