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

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

8 October 2024

Dr Peter Freemen

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

The Nature Genetics communication paper, has emphasised that around 6,000 UK children a year with rare genetic diseases never receive a diagnosis, many dying without the underlying cause being determined.

The researchers from the University of Leicester and University of Manchester also emphasise existing research that calculates the cost of pursuing lengthy diagnostic journeys for 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, is being used by leading medical journals to give each variant a standardized name, allowing diagnostic evidence to be shared and found.

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

Dr Peter Freemen is the lead scientist who devised and developed VariantValidator. He is an honorary lecturer and formerly a PostDoc at the University of Leicester where he began development of the platform, and has a son with an undiagnosed genetic disorder.

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.

Dr Freemen said: "It's widely recognized that doctors often describe DNA variants using various outdated or non-standard naming systems.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 seven 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."