Seeking stability in gene nomenclature

Anne Paxton

April 2021—Human first names are not necessarily known for being meaningful—or unique for that matter. When Shakespeare’s Juliet muses, “What’s in a name?” she’s observing that her lover’s name is more or less an arbitrary label without relevance to the essence of Romeo.

Human gene names, by contrast, cannot be arbitrary. Because the stakes of adopting the right gene name are high, gene nomenclature standards ensure that a lot of essence is conveyed by what is literally “in” each human gene’s name.

Fei Yang, MD, assistant professor of pathology at Oregon Health and Science University, knows a great deal about the need for sound gene nomenclature. In her work as a clinical molecular geneticist with Knight Diagnostic Laboratories, she performs next-generation-sequencing–based mutation screening panels for patients with leukemia and other hematological malignancies to help clinicians choose the best treatments. “I deal with genes every day,” Dr. Yang says. “All the time.”

“Detecting gene mutations plays an increasingly important role in the clinical management of cancer patients,” says Dr. Yang, a member of the CAP/ACMG Biochemical and Molecular Genetics Committee. “In co-management of patients, we have people with different expertise”—oncologists, clinical laboratory personnel, and clinical and basic researchers. When gene mutations are discussed, “It is of the utmost importance that we all know we are referring to the same gene,” she says.

That has made stability a central goal of gene nomenclature. But there’s much more to the nomenclature process than achieving stability.

The HUGO Gene Nomenclature Committee (HGNC), an international, voluntary standard-setting committee of the Human Genome Organization (HUGO), aims to ensure that for research and clinical purposes, the symbol and name of any individual human gene succinctly convey as much as possible about their unique subject and avoid as much confusion as possible when used.

Since its launch, the HGNC has issued a series of updated guidelines for the naming of human genes. The goal has been to reflect the major changes and the increase in knowledge and data in human genomics.

Having named some 42,000 human loci to date, and facing a constant stream of novel human genes ready for naming and existing genes that might be renamed, the HGNC has regular updating to think about. But at the same time, the organization strives, in the interest of consistency and stability, to make minimal changes to gene nomenclature.

“Two years ago, I started to design an NGS-based clinical assay to target genes associated with germline cancer predisposition to myeloid malignancies,” Dr. Yang says. “One of the genes, EFL1, is associated with an inherited condition called Shwachman-Diamond syndrome, and it has been associated with an increased risk for developing pancytopenia and malignant transformation to MDS or AML.”

“But when I communicated with the company that was helping me design the sequencing primers, this gene could not be taken up into their system.” Later, she found out that the company was using an older gene symbol for this gene: EFTUD1. The correct name was the one Dr. Yang was using.

“So that caused a problem when I designed the assay. And I had to find another way to be able to communicate with the company.”

“In the situation where some of the older gene nomenclature was replaced by a new one, a clinician may get the old nomenclature of some genes based on publications. And when we, as a laboratory, report a gene mutation with a new gene nomenclature, we may seem to be talking about different things, but we’re not. So it hampers our communication.”

As a result, she supports the aim to standardize gene names—but she notes there is a downside. “I would appreciate it if the incidence of changing the gene nomenclature could be kept at a minimum. Changing gene nomenclature could impact the communication of clinical labs with physicians in reporting the test results, for example.”

A good example of such a problem, Dr. Yang says, relates to the KMT2A gene. “This is the gene symbol currently approved for a gene previously known as MLL. It’s a well-known prognostic biomarker for acute myeloid leukemia. Alterations involving MLL define a subtype of leukemia with aggressive disease course and suboptimal outcome when treated with conventional chemotherapy.”

“This gene has been researched for over 30 years and a lot of data has been published under the gene symbol of MLL. It is noticeable that MLL is still a preferred gene symbol both in the recent literature as well as among oncologists.”

“But since the gene symbol change to KMT2A two or three years ago, nowadays when we issue the report we have to use KMT2A and then put MLL in parentheses afterward in order to avoid confusion and to facilitate communication.”

A name change could explain why a pathologist might not understand a particular gene name, she says, making it important to keep current on what is happening with the naming of genes.

As research continues, there will be increasing room for use of the HGNC gene nomenclature, Dr. Yang says. “More and more genes are being discovered by research to be associated with certain conditions and to have clinical utility in dealing with those conditions.”

For Karen Tsuchiya, MD, the issue of gene nomenclature first arose when she was a member of the CAP Cytogenetics Committee, and it was about the KMT2A(MLL) gene symbol. “One of my colleagues brought it up. It was shortly after the KMT2A gene symbol was changed from MLL, which it had been for many years,” says Dr. Tsuchiya, associate professor of laboratory medicine and pathology, University of Washington School of Medicine.

Her colleague was concerned about the change. “He had had some experiences and found it potentially created patient safety issues if the people you’re writing the report for don’t know that the gene name and symbol have changed. There was so much literature that used the MLL gene symbol, and that was what all the oncologists were familiar with.”