There’s a new database of all the known genetic variants that cause XLH (not the autosomals, which need their own database), and you can read about how it was created in a new journal article in Human Mutation.
Here’s the explanation for why the database is so important: “Early and accurate diagnosis is beneficial for XLH patients as treatment leads to dramatic reduction in morbidities and improvement in patient quality of life. However, this is complicated by the rarity of the disease, phenotypic variability, similarities to other forms of congenital and sporadic hypophosphatemias, and the absence of a comprehensive source of PHEX disease‐associated variants needed for accurate and timely interpretation of genetic testing results.”
I found it interesting that only a few years ago, the standard talking point was that there were about 300 known variants to the PHEX gene (section that regulates phosphorus) that cause XLH, and now they’ve documented close to three times as many — 870! With more to come as they’re identified.
Something else in the article that reflects a recent change in scientific talking points is the use of the term “pathogenic variant” instead of “mutation.” The journal itself is still called Human Mutation, but just as many patients prefer the term “disorder” to “disease” in order to avoid unnecessarily negative connotations, the scientific community is coming around to recognizing the impact of the negative connotations of “mutation” (it makes us think of zombies and other scary science fictional creatures). To avoid that scary and often inaccurate connotation, scientists are replacing the term with the judgment-neutral term, “variant.” Then, an adjective is added to establish whether the variant is either benign (harmless) or pathogenic (causing adverse consequences). Thus, instead of saying XLH is caused by a gene mutation, the better terminology is to say that XLH is caused by a pathogenic variant.
Yeah, “pathogenic variant” a mouthful, but it’s the same number of syllables as X-Linked Hypophosphatemia, so if you can say that, you can say the other, with practice! Of course, in non-scientific settings, dealing with friends or family, it may be easier to just say XLH is caused by a genetic mutation instead of having to explain what a pathogenic variant is. But in more formal settings, it’s better to use “pathogenic variant.” This is particularly true in scientific literature, where accuracy is key, and in genetic counseling sessions, where the patient/parent is already under significant stress, and doesn’t need to be thinking that they (or their potential children) are some sort of mutant creature from science fiction!
As explained by Penn Medicine, “By definition, a mutation does not imply the change is damaging, advantageous, or neutral. Although, many deep-seated cultural references have established a negative connotation to the word mutation; this has also lead to the inaccurate assumption that every gene mutation is harmful or disease-causing. This left the genetics community with a need to help categorize genetic changes and also help clearly communicate whether certain genetic mutations are harmful or just simply exist without impacts.”
I’ll probably slip occasionally in the future and refer to XLH as being caused by a gene mutation, but I’m trying to be conscious of the better terminology, and I hope you will too. Because, as I’ve said many times in the context of the misuse of “rickets” to describe the chronic hypophosphatemias, words do matter.
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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