January 17, 2018  |  Human genetics research

SOLVE-RD Funded to Improve Diagnosis of Rare Disease with New Tools Including Long-Read Sequencing

The SOLVE-RD research program, a collaboration of 21 participant organizations in 10 nations, announced it has received a €15 million grant from the European Union’s Horizon 2020 initiative. SOLVE-RD aims to improve the diagnosis and treatment of rare diseases, which in total affect millions of Europeans. The program is applying novel diagnostic tools to around 19,000 cases unsolved by prior short-read exome sequencing. Prominent among the planned “multi-omics” approach is long-read genome sequencing, which will reveal the large amount of potentially disease-causing genetic variation that is not accessible with short-read DNA sequencing. SOLVE-RD plans to apply long-read genome sequencing to 500 cases.

Recent studies with PacBio long-read genome sequencing have shown that each human genome has upwards of 20,000 structural variants (differences ≥50 bp), which affect more base pairs than single nucleotide variants and small insertions and deletions together [1]. Short-read sequencing fails to detect most of these structural variants, which often lie in repetitive regions of the genome or are larger than short reads can span [1]. In 2017, Merker et al. reported the first use of PacBio long-read genome sequencing to identify a disease-causing structural variant in a Mendelian disease case undiagnosed by short-read genome sequencing [2]. The study applied low (8-fold) coverage sequencing on the Sequel System to discover structural variants. By applying long-read sequencing to a larger cohort of subjects with rare diseases, the SOLVE-RD program promises to provide valuable insights into the disease classes for which this technology is most useful. At ASHG 2017, Han Brunner, a coordinator of the SOLVE-RD consortium, described initial work on this effort using the Sequel System.

[1] Huddleston J, et al. (2017). Genome Research, 27(5):677-685.
[2] Merker JD, et al. (2018). Genetics in Medicine, 20(1):159-163.

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