Long-read genetic sequencing has been able to reveal the root cause of several rare diseases that have been impossible to find using short-read technology, researchers report.
The findings demonstrate the clinical value of long-read sequencing, which is becoming increasingly feasible with improving technology and falling prices.
Researchers at the Radboud University Medical Center used PacBio’s Revio platform and HiFi long reads which was recently presented at the J.P. Morgan Healthcare Conference to investigate 100 cases in which the genetic causes of rare diseases were challenging or impossible to identify in previous studies.
The technology allows sections of 20,000 genetic “letters” to be read compared with just a few hundred possible with short reads.
It was able to identify 93% of the pathogenic germline variants that had been missed using the short-read approach, according to the study published in the American Journal of Human Genetics.
These included complex structural variants and DNA methylation abnormalities.
Senior researcher Christian Gilissen, PhD, told Inside Precision Medicine he saw many advantages with long-read over short-read sequencing, particularly for medical genetics involving rare diseases.
“I think long-read sequencing technology is really [the] future of medical genetics, and this technology has the potential to replace many of the other techniques that we are currently using,” he explained.
Of the more that 7000 rare diseases currently known, more than 70% are genetic in origin.
Several of these have been identified using short-read technology, in which DNA is cut into small pieces around 300 letters to be analyzed, before being reassembled until the complete human genome of around three billion letters is mapped.
While this has been able to identify several genetic diseases, there are downsides and it is not always possible to reposition the pieces in the correct places.
This is particularly true for long, repetitive DNA repeats and also with translocations, where the genetic material has been deleted, inserted or rearranged.
It means that other technologies often also need to be deployed to improve its accuracy, leading the researchers to look into other options.
Long-read technology immediately identified 83% of the genetic causes behind these diseases, which included around 90% of structural variants, single-nucleotide variants/insertions or deletions in homologous sequences, and expansions of short tandem repeats.
A further 10% were detected using the technique but not automatically identified, said Gilissen.
He told Inside Precision Medicine: “Our laboratory is working on the implementation of long-read whole genome sequencing for genetic diagnostics and will start offering this in the current year.”
