International research led by the University of Oxford, University of Manchester, and Genomics England suggests global guidelines for rare disease diagnostics should be updated to include disease-causing non-coding variants.

Until recently, most rare disease testing has focused on genetic variants in the coding regions of the genome, and the majority of testing guidelines reflect that. However, coding regions only account for a small amount of the genome and non-coding variants can also cause disease through their impact on gene regulation and expression.

With the decreasing cost and improving quality of genetic testing and sequencing, more standardized testing for non-coding variants is becoming a reality. “Whole genome sequencing has been shown to have the potential to increase diagnostic yield and includes detection of variants in a wide range of regulatory regions, as well as variants in genes encoding non-coding RNAs,” write the researchers in the journal Genome Medicine.

“Analysis of whole genome sequencing data, however, often excludes variants that fall in non-coding regions of the genome or classifies them as variants of uncertain significance, primarily due to difficulties in predicting or determining their impact.”

A group of nine U.K. experts, including representatives from Genomics England aimed to try and better define non-coding variants and to add this information to international guidelines to help improve testing in future.

Once the new guidelines were drafted, a larger group of experts including those from the Broad Institute in Cambridge, Massachusetts, and the Garvan Institute and Murdoch Children’s Research Institute in Australia, among others, tested their usability.

The findings of the study suggest that to avoid problems in interpretation, testers should focus on non-coding variants that fall into regulatory elements of known target genes and those with a documented link to the phenotype or disease of interest.

They also suggest that the lists of variants being tested for should continuously be updated and revised depending on the findings coming from research studies to make sure they remain clinically relevant.

“We are very pleased to be able to present these recommendations to the global clinical and scientific community,” said Jamie Ellingford, lead genomic data scientist for rare disease at Genomics England, Research Fellow at The University of Manchester, and co-lead of the study.

“We hope that their adoption will serve as a useful starting point for standardizing and refining the characterization of ever more variants of unknown significance. In doing so we believe that we will be able to target a subset of variants of unknown significance, and provide guidelines for how to create appropriate functional evidence to interrogate pathogenicity for these variants and deliver more diagnoses for patients in the U.K. and around the world.”

The recommendations were presented at the Association for Clinical Genomic Science meeting in late 2021 for further feedback, and will also be discussed at a workshop at the American Society of Human Genetics annual meeting in Los Angeles in October.

Also of Interest