Implementation of exome sequencing for rare undiagnosed diseases in LMICs: the G2MC rare diseases exome sequencing pilot project.

Rare undiagnosed diseases impose a substantial burden on patients, families, and health systems. Collectively they affect an estimated 300-350 million people worldwide. Of these, approximately 250 million live in low- and middle-income countries (LMICs). Many rare diseases have a genetic basis and can be diagnosed using molecular testing. However, patients in LMICs often lack access to advanced diagnostics and specialist care, leading to prolonged diagnostic odysseys and significant distress. To address this gap, the Global Genomic Medicine Collaborative (G2MC) implemented a Rare Disease Pilot Project to enable clinical genomic testing at six LMIC sites (Chile, Malaysia, Mexico, Nepal, South Africa, Sri Lanka). Using trio exome sequencing for 18 selected families, supplemented by chromosomal microarray as indicated, definitive molecular diagnoses were established in 5 families (pathogenic/likely pathogenic variants explaining the phenotype). An additional 8 families had suspected molecular diagnoses with strong phenotype correlation that require functional validation, while 5 families remained undiagnosed at the end of the pilot. The integration of genomic data into clinical decision-making enabled definitive diagnoses, precise management, and genetic counseling for these patients. The pilot also strengthened local capacity building by conducting cross-site case conferences and enabling local reanalysis of sequence data at sites with bioinformatics capabilities. This study demonstrates the feasibility, effectiveness, and adaptability of implementing exome sequencing in resource-limited settings and highlights its potential to transform rare disease diagnosis and care in LMICs.