There have been described, to date, around 7,700 distinct rare diseases (RD), affecting approximately 400 million individuals worldwide, which accounts for about 4% of the global population. Approximately half of those diagnosed with a RD are children, and one third of them will die before reaching the age of 5. There is an estimation that in Europe, less than 10% of patients with a rare disease undergo medical treatment and only 1% receive an approved treatment plan, making this one of the major global health challenges for the 21st century. The majority of RD are predominantly caused by rare variants in a single gene (monogenic) and the identification of these causal variants provides a clinical diagnosis for patients with a suspected rare Mendelian disorder.

Recent advancements with high-throughput sequencing technologies have revolutionized diagnostic capabilities, mainly through the prevailing utilization of whole-exome sequencing (WES) in clinical routine diagnostics, and more recently surveying the entire genome with whole-genome sequencing (WGS). Nevertheless, due to yet unknown disease genes as well as the limitations of conventionally employed technologies and analysis tools in detecting certain variant types, more than half of the patients remain undiagnosed.

For those patients with negative WES/WGS results, profiling the transcriptome with RNA-seq is a valid option for gene prioritization, since the yet to be discovered causal variant (e.g., VUS variant) might affect gene expression or splicing. Adoption of long-read WGS is also advantageous, e.g., complex structural variants, repeat expansions or transposable elements insertions can be more easily inspected and enables direct measurement of DNA modifications. We anticipate that screening the simultaneously, the genome, the transcriptome and the epigenome of patients with a suspected monogenic disease, and investigating intercorrelations among the different omic layers, might lead to the discovery of novel causative components in some conditions, and probably providing additional diagnostic yield. By that means, the Omics-RD project aims to apply an innovative multiomic strategy to detect outlier events with RNA-seq (aberrant expression, aberrant splicing and monoallelic expression), previously missed structural variants and aberrantly imprinted loci with long-read WGS in a large cohort of unsolved Spanish RD patients. The project will also evaluate the impact of using the newly released Telomere-to-Telomore human reference assembly for the discovery of new disease genes or novel mutations in known clinically relevant genes.

Grant PID2021-125158OA-I00 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU.