Integrative omics approaches to advance rare disease diagnostics

Over the past decade high-throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease-causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA-sequencing, proteomics, metabolomics and DNA-methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.

Automated summary

Over the past decade, high-throughput DNA sequencing approaches, such as whole exome and whole genome sequencing, have become standard procedures for diagnosing Mendelian diseases. However, the diagnostic rates vary widely and many patients remain undiagnosed. Advances in omics technologies and computational analysis offer opportunities to increase the diagnostic rates by providing evidence for disease-causing variant validation and prioritisation. This review provides an overview of the current application of various omics technologies for the diagnosis of rare genetic diseases, particularly inborn errors of metabolism.