Image Credit: Scientific Frontline
Scientific Frontline: "At a Glance" Summary: Imprecise Gene and Mutation Naming
- Main Discovery: A systematic review of scientific manuscripts revealed a universal failure to accurately name critical gene mutations, with not a single paper applying standardized genomic nomenclature correctly.
- Methodology: Researchers analyzed 52 scientific papers submitted by multiple scientists to the Genetics in Medicine Journal over a two-year period to evaluate the precision and accuracy of gene and variant naming conventions.
- Key Data: Every analyzed manuscript contained at least one naming error, a widespread inaccuracy that directly contributes to the 70% of rare genetic diseases that currently go undiagnosed.
- Significance: Inconsistent variant naming severely impedes the discoverability of diagnostic evidence in databases and routine searches, leading to missed diagnoses, incorrect clinical management, and avoidable healthcare costs reaching billions of dollars per decade.
- Future Application: These findings are driving the development of a new global professional standard led by the American College of Medical Genetics and Genomics to enforce strict, minimal acceptable standards for variant data in clinical reporting, literature, and databases.
- Branch of Science: Clinical Genomics and Medical Genetics
- Additional Detail: Experts strongly recommend universally adopting automated naming tools, such as VariantValidator, and enforcing strict nomenclature compliance during the peer review process to prevent critical data from being lost.
A systematic review of 52 scientific papers submitted to a world-leading clinical genetics journal from multiple scientists over a two-year period reveals that not even one named critical gene mutations (correctly termed as variants) with precision.
The findings partly explain why around 70% of rare diseases go undiagnosed, even in the UK, which arguably has the world's most advanced genomic medicine service.
Led by Dr Peter Freeman, a geneticist from The University of Manchester, the findings are published by the Editorial team at the Genetics in Medicine Journal (GIM)- considered a world-leading clinical genetics journal - in Clinical Chemistry
It is frustrating news for the parents of the 6,000 or so UK children a year with rare genetic diseases, most of whom never receive a diagnosis, and many dying without the underlying cause being determined.
Correct nomenclature - as it is known - could also reduce the cost to the NHS of pursuing avoidable lengthy diagnostic journeys into rare genetic diseases - thought to be over £3 billion per decade.
Miscommunication caused by inconsistent genetic naming has, over time, led to documented cases of incorrect clinical management.
The researchers found that every manuscript submitted to the Genetic in Medicine Journal (the journal of the American College of Medical Genetics and Genomics (ACMG), who develop global professional standards in Clinical Genomics), contained one or more errors.
That, they say, substantially reduced the probability of finding variants during routine searches. Such searches are required to gather diagnostic evidence, but if the evidence cannot be found due to findability issues, then a diagnosis may be missed.
The research is being incorporated into a new ACMG-led professional standard, which is being collaboratively developed with all the major professional societies and quality assurance bodies across the US, EU, UK and Canada, to be announced later this year.
The standard will govern the minimal acceptable standards for variant data in clinical reporting, databases, and literature.
Such standards have been legally binding in the United States but there is no indication yet that the UK will follow suit; however, the quality bodies that control UK genomic medicine standards are part of the ACMG-led coalition.
Dr Freeman, formerly of the University of Leicester, and now based at The University of Manchester devised a tool called VariantValidator to give each variant a standardized name, allowing diagnostic evidence to be shared and found.
Working with the Human Genome Organization, the Genetics in Medicine (GIM) editors assembled a technical editing team led by Dr. Freeman to develop instructions for authors on proper variant reporting.
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), and widely used AI discovery tools from identifying critical evidence and adding literature to ClinVar and LOVD records.
"The language of genomics, which guides everything from discoveries of gene-disease associations to rare disease diagnosis, relies on an established standardized system of naming genomic variants. This study has revealed a shocking level of inaccuracy in the naming of genetic variants- which has real-world consequences. Me and my team have yet to find a journal article which uses the correct nomenclature and did not require intervention"Dr Peter Freeman
Dr Freeman, whose son has an undiagnosed genetic disorder, said: “The language of genomics, which guides everything from discoveries of gene-disease associations to rare disease diagnosis, relies on an established standardized system of naming genomic variants.
“This study has revealed a shocking level of inaccuracy in the naming of genetic variants- which has real-world consequences. Me and my team have yet to find a journal article which uses the correct nomenclature and did not require intervention.”
He added: “Doctors almost always describe DNA variants using various outdated or non-standard naming systems or fail to accurately apply the current standard. This means they are publishing data, which is less findable, so may be missed by others in the field attempting to reach a diagnostic decision, denying the possibility of treatment.
“But even more importantly, for children like my son, not having a diagnosis means they cannot access the support services they desperately need to support their wellbeing and development.
“Nomenclature should accurately describe the changes in DNA sequencing observed when there is a genetic variant. 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 team recommend:
- Universally adopting gene/variant nomenclature guidelines within published works.
- Implementing robust peer review processes to enforce gene/variant nomenclature standards.
- Supporting automated submission of structured variant and classification data into publicly available repositories
- Work with publishers to educate production and copyediting teams.
What misnaming means for patients
In an infamous example over decades, laboratories and clinicians used conflicting naming systems for Factor V Leiden, a common inherited genetic mutation that causes thrombophilia,
That resulted in misinterpretation of patients’ thrombosis risk and inappropriate treatment decisions.
In another example, inconsistent reporting of variants of the gene CFTR in cystic fibrosis has contributed to misunderstandings of carrier status and disease risk, leading to errors in family‑planning counselling for affected couples.
Published in journal: Clinical Chemistry
Title: Universal Presence of Gene/Variant Nomenclature Errors in Journal Manuscript Submissions
Authors: Lisa A Lansdon, Binu Porath, Mari Mori, David T Miller, Diane Dunham Drexler, Catherine Wattenberg, Morgan Richardson, Robert D Steiner, and Peter J Freeman
Source/Credit: University of Manchester
Reference Number: geno030926_01
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