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Improving Clinical Diagnostics of Repeat Expansion Disorders with Combined Short and Long-Read WGS
At Variantyx, we are constantly pushing the boundaries of genomic technology to ensure our patients receive the most accurate and comprehensive diagnosis possible. One key area of focus is short tandem repeats (STRs) that can cause complex neurological disorders. While short-read WGS has proven to be a powerful and cost-effective technology for analyzing these variants, it has challenges.
The challenge of analyzing STRs with short-read sequencing lies in its read length constraints. Short reads, typically limited to 150 base pairs, fail to span larger variants and can result in ambiguous mappings in repetitive genomic regions. This is especially problematic for pathogenic STR repeat expansions, which frequently extend beyond short read lengths. Plus STRs are highly variable, with differences not only in the number of repeat units but also in the composition of the repeat loci. With short-read sequencing, it can be difficult to impossible to determine their exact size and composition.
Earlier this week, an article by Lucy Kaplun, our Director of Advanced Development, was published in the International Journal of Molecular Sciences, highlighting our work in combining short-read and long-read WGS to improve the analysis of repeat expansions.
Our research, as outlined in the article, demonstrates that combining short-read WGS with Oxford Nanopore Technologies (ONT) long-read sequencing significantly improves the diagnostic performance of genetic testing for neurological disorders that are caused by repeat expansions. By using both short-read and long-read sequencing, we can differentiate between pathogenic, premutation, intermediate, and benign repeat expansions, even in cases with longer repeat stretches (including FGF14, FXN, FMR1 and RFC1). Additionally, this combined approach allows us to analyze the composition of repeat loci, somatic mosaicism and methylation status when relevant.
By pioneering this two-tiered sequencing approach, we are fully leveraging the advantages of long-read sequencing while maintaining simple and efficient laboratory and analysis processes. This approach allows us to keep costs reasonable while ensuring that we provide the most accurate and detailed genetic diagnoses possible.
Read the full article for a deep dive into our methodology.