Implementation of a medical genomics program for rare diseases in Uruguay

Rare diseases (RDs) affect an estimated 7% of the global population and comprise ~7,000 heterogeneous conditions, most of which have a genetic etiology. Despite their collective burden, RDs pose major diagnostic challenges, often resulting in prolonged diagnostic odysseys with substantial clinical, emotional, and economic consequences. Next generation sequencing technologies such as whole exome (WES) and whole genome sequencing (WGS) have transformed RD diagnostics in high-resource settings. In contrast, the use of such technologies in Latin America remains uneven due to structural, regulatory, and economic constraints. In addition, the underrepresentation of admixed populations in genomic databases further complicates variant interpretation, reducing the diagnostic yield. In this context, we created the first genomic medicine program for rare diseases in Uruguay to address these challenges by implementing next-generation sequencing (NGS) strategies for diagnosis.

Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed on a cohort of 203 patients with suspected RD belonging to the Uruguayan public healthcare system. Variant prioritization was conducted using established bioinformatics pipelines integrating population frequency filtering, inheritance models, functional impact, and phenotype-driven clinical interpretation. Implementation of population-aware variant interpretation strategies was critical in this admixed population, helping to reduce false-positive findings arising from the underrepresentation of Latin American populations in global reference databases. This framework was built through sustained collaboration between academic institutions and healthcare providers, with a strong emphasis on local capacity building in clinical genetics, molecular diagnostics, and bioinformatics.

To date, we have analyzed a total of 203 patients: 172 using WES, 29 using WGS, and 11 using mitochondrial DNA sequencing (9 of whom were also analyzed by WES). The overall diagnostic yield was 48% for WES and 31% for WGS. The program significantly shortened diagnostic trajectories and enabled actionable clinical insights in a substantial proportion of cases.

Our experience shows that comprehensive genomic diagnostics for RDs can be successfully carried out in emerging genomic medicine settings through integrated workflows and sustained investment in human capital. This initiative represents a scalable model for other low income countries seeking to incorporate genomic medicine into public healthcare systems and highlights the importance of regional genomic data to improve diagnostic accuracy and equity.