HGNC Interaction with Patient Groups

Increasing HGNC Interaction with Patient Groups

The HGNC is keen to engage with patient groups when possible, as their input can help us to assign meaningful, functionally informative and importantly, non-pejorative gene nomenclature.

Discussions with The Barth Syndrome Foundation

We have discussed the nomenclature update for TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) in a previous blog post. In brief, the previously approved symbol for this gene, “TAZ” has been updated to TAFAZZIN, with support from the research community and the Barth Syndrome Foundation. This reduces confusion caused by the alias “TAZ” being commonly published for the unrelated gene WWTR1 (WW domain containing transcription regulator 1). This topic is also discussed further in our commentary paper “The risks of using unapproved gene symbols” (October 2021) published in AJHG. In this paper we discuss several examples of cases where genes have been confused due to either the use of shared alias symbols or because an approved symbol clashes with an alias.

Discussions with the European Fragile X Network

We more recently discussed gene nomenclature with representatives from the European Fragile X Network. A 2022 paper from Herring et al that discussed the continued use of the offensive term “retardation” in the literature and how this risks stigmatization of those affected. They endorsed the removal of all references to ‘retardation’ from gene nomenclature and their proposal included removing the letter ‘R’ within gene symbols in which it once stood for ‘retardation’. The HGNC published a response to this paper in which we acknowledged that although we had previously removed reference to “retardation” in the approved gene names of FMR1, ATRX and AMMECR1, we had unfortunately overlooked updating the full name of the FRAXA fragile site up until more recently.

The “fragility” associated with Fragile X syndrome is due to an unstable repeat of three nucleotides (CGG) which is found in the 5′ untranslated region of the FMR1 gene. A considerable expansion of this repeat can silence the expression of FMR1, potentially resulting in the range of characteristics associated with fragile X syndrome.

While we appreciated why Herring et al called for the removal of the letter R from the FMR1 gene symbol, we explained that we felt unable to do this as the unique FMR1 symbol is heavily entrenched in the literature. We originally adjusted the gene name from “fragile X mental retardation 1” to “FMRP translational regulator 1” in YEAR. Following further discussion with the authors and an in-depth look at papers published on the function of the FMR1 encoded protein, we were able to propose and ultimately change the name of this gene to the non-pejorative and functionally informative “fragile X messenger ribonucleoprotein 1”.

The AFF family members all had the gene name “AF4/FMR2 family member #”, but we could appreciate that referencing “FMR2” in these gene names was not ideal. Again, the literature surrounding these genes provided an alternative name for this family that was already used in a number of publications: the “ALF transcription elongation factors”. While the ALF acronym is derived from the gene aliases/previous symbols “AF4” (approved as AFF1), “FMR2” (approved as AFF2), and “LAF4” (approved as AFF3) we feel that this is suitably removed from the original derivation of FMR2 and hence has no negative associations.

To summarise, the HGNC made some changes to the nomenclature and recommended the following:

Discussions with Researchers from an International Working Group on Gaucher Disease

We were contacted in 2021 by a researcher studying the molecular mechanisms underlying Gaucher disease. This phenotype can be associated with an enlarged spleen and liver, thrombocytopenia and bone disease in patients.

The researcher asked if we could add a “1” to the symbol for the gene associated with mutations linked to Gaucher disease . Updating GBA (glucosylceramidase beta) to GBA1 would bring its nomenclature into line with the two other genes encoding glucosylceramidases, GBA2 (glucosylceramidase beta 2) and GBA3 (glucosylceramidase beta 3 (gene/pseudogene)). This set of genes is a functional grouping and they are not paralogs.

This proposed update of GBA to GBA1 was supported by the board of the International Working Group on Gaucher Disease (IWGGD) which was previously the European Working Group on Gaucher Disease (EWGGD). The IWGGD brings together clinicians, scientists and patients in an open forum for discussion on all aspects of the condition. They are linked to the International Gaucher Alliance (IGA) patient group. The IWGGD discussed the proposed change at their first symposium in Leiden in the Netherlands in May 2022 and it was well received. This was a great opportunity to gauge support across many interested parties.

We also consulted with authors who had previously published on this gene and the vast majority of respondents were also supportive of the proposal. Most felt it would reduce confusion and reflected that fact that many researchers were already using GBA1. An added bonus is that the new symbol is more specific for searching the literature – no more false hits from clashes with other abbreviations for irrelevant concepts like gut-brain axis. The nomenclature has now been updated.

Support Groups and Gene Nomenclature considerations

There are multiple cases where patient support groups and advocacy organisations have been set up that make reference to one or more gene symbols, if variants of a gene or genes in question have been associated with a phenotype. This is something we try to be aware of when reviewing gene symbols of clinical relevance, and as we look to permanently stabilise medically relevant gene symbols.

Some of the many examples of support groups directly referencing gene symbols, names or gene root symbols in their group names include:

Links sourced from the Genetic Alliance UK and NORD (the National Organization for Rare Disorders).

Further links to worldwide non-governmental patient organisations focused on rare diseases can by found via the EURORDIS alliance website.

Of course, even in cases where gene symbols are not included in patient support group names, they are still very likely to be mentioned in the information provided to clinicians and patients. Stabilising gene symbols related to Mendelian diseases is a current key aim of the HGNC.

If you are a member or representative of a patient support group and would like to get in touch with the HGNC about a nomenclature issue, please email us as we are keen to engage with you.