RARE Daily

Scientists Leverage Genomics England Data to Improve Rare Disease Diagnosis

July 20, 2022

An international group of scientists have published recommendations for updating existing standards for determining the disease-causing potential of genomic variants, harnessing insights from Genomics England rare disease participants.

The proposed expanded guidelines will enable clinicians and researchers to take better advantage of the full range of variation in whole-genome sequence data. Scientists at Genomics England led the work, which included an expert team of scientists and clinicians from academic and healthcare institutions across the United Kingdom, United States, and Australia. They published the recommendation in a paper in the online edition of the open-access journal Genome Medicine.

“Our aim is to catalyze getting more valuable genetic diagnoses to patients,” said Nicky Whiffin, group leader and Sir Henry Dale fellow at the University of Oxford, and co-lead of the study. “As we have access to more and more whole genome sequencing data it is becoming increasingly clear that variants in regions of the genome that do not directly encode protein play an important role in rare disease. These recommendations enable us to fully interpret these variants and harness them in the clinic, improving diagnosis and personalized treatment.”

To date, most genetic testing has been focused on coding sequence variants that disrupt regions of genes that directly encode proteins. The standards and guidelines developed over the past decade for interpreting the results of these tests—including single-gene assays, gene panels, and whole-exome sequencing—have focused on these types of variants.

While these standards have provided an evidence-driven framework for delivering consistent and reliable diagnoses using such tests, coding regions make up no more than 2 percent of the genome. With the advent of affordable WGS and its growing use in clinical practice, ever larger numbers of potentially disease-causing variants of many different types are being detected, but without similarly systematic criteria for the community to assess their impact on disease.

As a result, the researchers said there has been a proliferation of “variants of uncertain significance,” some of which have the same downstream clinical impact as pathogenic coding variants but work through different mechanisms and so are more difficult to assess.

In proposing updates to these guidelines for the WGS era, the authors focused on recommending adaptations and expansions that sit alongside the existing guidance and using the same strategy of consultation and consensus-building that was used to create them.

The researchers hope the adoption of the recommendations will serve as a useful starting point for standardizing and refining the characterization of ever more variants of unknown significance.

“Even with the great improvements brought with new sequencing technologies and the interpretation of DNA variation, many families remain without a diagnosis, often for years. Work like this is vital to changing that, allowing identification of causes of disease that have been hard to identify, hiding between the genes,” said Rich Scott, chief medical officer at Genomics England. “This paper illustrates both the increasing power of the technology. It also emphasizes the importance—with participants’ consent—of linking clinical care to research at national scale.”

Author: Rare Daily Staff

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