Enhancing rare disease diagnosis through multi-omics

Rare diseases comprise over 7’000 disorders, affecting approximately 400 million people worldwide and 500’000 individuals in Switzerland. Due to their typically early and severe onset, rare diseases disproportionately affect children, often leading to premature death or lifelong disability. Current diagnostic procedures are slow, low-yield, and offer limited insight into disease pathogenesis—highlighting the urgent need for new approaches

In partnership with the PHRT and the Swiss Multi-Omics Center (SMOC), we are pioneering rare diagnosis using multi-omics. Through whole genome sequencing (genomics), RNA sequencing (transcriptomics), and proteotyping (proteomics) alongside phenotypic and biochemical profiling (phenomics), we found a molecular diagnosis for 177 out of 210 cases of the rare metabolic disorder methylmalonic aciduria, and in 101 out of 150 individuals with a suspected remethylation disorder. Further investigations revealed a correlation between disease severity and disturbed energy metabolism in methylmalonic aciduria, evidenced also in cellular and animal models of disease, and disturbed translation in remethylation disorders. This multi-omics approach is now being used to modernize and improve rare disease diagnostic assays in our hospital.

As part of the National Data Stream SwissPedHealth, we are further developing a multi-omic workflow to diagnose rare diseases in critically ill children. We have initiated a Swiss-wide, prospective trial, encompassing all five Pediatric University Hospitals, which has already recruited over 75 patients. Genomic, transcriptomic, proteomic and metabolomic investigations in 37 individuals—including 23 undiagnosed by standard-of-care—illustrate both the challenges and opportunities of such an approach.

Overall, we are helping demonstrate the power of multi-omic based approaches to transform rare disease diagnosis, by increasing diagnostic rates and facilitating disease discovery, with the ultimate goal of supporting timely, life-saving therapies.