Cutting corners results in rare genetic diseases being undiagnosed, say scientists

Inaccurate naming of genetic diseases is resulting in some rare genetic diseases needlessly being undiagnosed, University of Manchester scientists warn. 

The Nature Genetics communication paper, published today (02/10/24 have throws into sharp relief existing data that around 6,000 UK children a year with rare illnesses never receiving a diagnosis, many dying without knowing what caused them 

The researchers also emphasise existing research that calculates the cost of pursuing lengthy diagnostic journeys rare genetic diseases to the NHS is over £3 billion per decade. 

Hospital geneticists rely on published evidence to make diagnoses, but because of inconsistent variant naming, say the authors, they are often unable to locate relevant information, even if it exists. 

Many geneticists, they say, are using simpler but less accurate nomenclature, preventing databases like ClinVar and the Leiden Open Variation Database (LOVD) from properly identifying and adding literature to their records. 

However, a system called VariantValidator devised by researchers at the University of Leicester and now based at The University of Manchester is being used by leading medical journals to give each variant a standardized name.  That allows diagnostic evidence to be shared and found. 

In the communication paper the authors urge doctors to use the system to name genetic variants.

Though rare diseases, caused by variations in DNA sequences, affect fewer than 1 in 2,000 people the sheer number of rare genetic disorders at around 8,000 impact about 8%-10% of births worldwide.

Lead author Dr Peter Freeman from The University of Manchester, whose son has an undiagnosed genetic disorder, is lead scientist in the team that devised and develop VariantValidator.

He said: “It’s widely recognized that doctors often describe DNA variants using various outdated or non-standard naming systems.

“But the accurate naming of variants is crucial so that doctors can reference them and provide a diagnosis for patients with a genetic disorder.

“Sadly, many people, including my son, have not received the diagnosis they need which has difficult implications for them.

“For example without a diagnosis it can be very difficult to get a place at an appropriate school, or access desperately needed services.

“It’s galling to know that someone out there might have identified the variant which caused his illness, but may not have named it correctly so there’s no way of finding it.”

He added: “VariantValidator has been around for 7 years and is considered the gold standard in terms of naming genetic variants accurately so other clinicians will be able to find the definition and use them.

“But in a vast number of cases that is just not happening because it’s easier and quicker to cut corners or rely on outdated systems only recognisable in specific clinical disciplines.

“The problem is so widespread I’ve even come across experts responsible for setting clinical standards making these errors when naming variants in genetics focussed policy guidelines”.

“Our work is with the Human genome, but the nomenclature of genetic variants in viruses and other pathogens are also similarly non-standardised – and that’s also a problem which needs to be addressed.

“Nomenclature should accurately describe the changes in DNA sequencing observed when there is a variant when compared to a standard sequence. But in many cases, this is simply not happening and is part of a complex set of problems that is causing miss or missed diagnoses.”

The paper Standardising variant naming in literature with VariantValidator to increase diagnostic rates is available here