A new genetic sequencing panel could be used to help diagnose X-linked hypophosphatemia (XLH) and related conditions.
The panel was described in the European Journal of Endocrinology, in the study “Validation of a next-generation sequencing (NGS) panel to improve the diagnosis of X-linked hypophosphataemia (XLH) and other genetic disorders of renal phosphate wasting.” The study was funded by Kyowa Kirin, which sells Crysvita (burosumab).
Hypophosphatemic rickets (HR) is a broad term referring to conditions in which the kidneys excrete too much phosphate into the urine. This causes low levels of phosphate in the body, which leads to symptoms such as bone abnormalities.
XLH, the most common form of HR, is caused by mutations in the gene PHEX. To date, nearly 600 different mutations in this gene have been described.
XLH and other forms of HR share many of the same symptoms, and laboratory tests are often unable to distinguish between these rare conditions. Still, it is important for clinicians to be able to differentiate between different HR types — for example, Crysvita has been approved for XLH, but it may be ineffective or even harmful in other types of HR.
Traditionally, genetic diagnosis of XLH has been accomplished by sequencing the PHEX gene to look for mutations. By design, this approach is not able to detect types of HR caused by mutations in other genes.
In the new study, a team of researchers in Germany developed a next-generation sequencing (NGS) panel that determines the sequence of PHEX, as well as 10 other genes that cause other types of HR. The panel was able to process samples from 20 different individuals simultaneously, which, the researchers said, could reduce costs associated with doing such genetic tests.
To test their panel, the researchers analyzed samples from 50 people with diagnosed XLH whose PHEX mutations had already been determined using established methods. The novel panel was able to correctly identify the PHEX mutation in 49 of these samples.
“Since the NGS tool revealed a 100% agreement in 49 patient samples, the coverage and the sensitivity must be rated very high, proving that we created an easy, fast, and reliable diagnostic tool for the diagnosis of XLH,” the researchers wrote.
In the one sample that could not be identified by the panel, the mutation was a duplication of part of the PHEX gene. By design, NGS is not well-suited to detect this type of mutation so additional genetic testing would be required for people with such mutations, the researchers wrote.
They also tested samples from three people who had XLH-like symptoms, but in whom no PHEX mutations had been previously detected. In two of these people, the panel identified HR-causing mutations in other genes.
In the third individual, the panel revealed mosaicism in the PHEX gene. Mosaicism is a phenomenon in which a person has two or more sets of genetically distinct cells in the body.
“Since mosaic mutations are difficult to detect by [traditional sequencing], their description in PHEX is rare in the literature,” the scientists wrote. “Therefore, the identification of this mosaic mutation demonstrated the high sensitivity of the developed NGS panel.”
The panel has some inherent limitations, the most obvious being that since it analyzes 11 specific genes, HR-causing mutations in other genes would not be detected. As such, other technologies, such as whole-genome sequencing, may be necessary to detect such mutations, but they tend to be costly, the team said.
“The panel developed in this study seems to be a sensitive and specific tool which can not only detect mutations in PHEX, but also in other genes associated with HR,” the researchers concluded. “This differentiation is favourable for the patients as it readily leads to very specific treatment options.”
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