Reference Standards to Detect Large, Disease-Causing Genetic Variants Developed

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Although they are implicated in a number of serious diseases and conditions, large genetic mutations can be difficult to detect, something newly created reference standards for labs should solve.

So called ‘structural variants’ are often defined as genetic changes of 50 base pairs or more and have been linked to autism spectrum disorder, Huntington’s disease, cardiovascular disease, and other conditions. They are less commonly inherited than smaller variants, which often just consist of one base change, but can be harder to detect when testing.

It seems counterintuitive that it would be harder to find larger variants than smaller ones, but this is because “the most widely used sequencing technologies output relatively short strings of genetic code, making it hard to reconstruct what’s happening,” according to Justin Zook, Ph.D., a researcher at the National Institute of Standards and Technology in Maryland, USA. However, more modern sequencing methods are making it easier to find these large mutations.

A team of researchers led by Zook, have developed a series of test standards to help laboratory scientists to run more accurate diagnostic tests to detect these larger genetic variants.

As reported in the journal Nature Biotechnology, the researchers used genetic data from a well characterized family of Eastern European Ashkenazi Jewish ancestry and 19 different analysis approaches to define whether large mutations – mostly insertions or deletions – picked up on testing were accurate or not.

In total they compiled, more than 12,000 ‘calls’ that people running laboratory tests can now use to check whether they have accurately diagnosed an insertion or deletion of at least 50 base pairs using a specific test method.

“Just like a company making rulers could compare their ruler to a standard measuring stick to make sure it is measuring the correct distance, clinical laboratories doing DNA sequencing can measure National Institute of Standards and Technology reference material DNA and compare their answer to this new benchmark to help make sure they measure large insertions and deletions well,” said Zook.

This is the latest from the National Institute of Standards and Technology on genetic testing standards. Over the last 8 years the Genome in a Bottle Consortium – a collaboration between industry, academic and government scientists — has created similar standards for smaller inherited variants. The purpose of the consortium is to help standardize genetic testing and make it easier to roll it out on a larger scale and incorporate it into clinical practice more widely.

The authors acknowledge in their paper that they did not include complex structural variants and those they did not have defined sequence for. They say the next step for the consortium will be to try and characterize more complex regions, such as those containing repetitive sequences.

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