A study of Chinese children with X-linked hypophosphatemia (XLH) found 28 new mutations in the PHEX gene that cause the rare and progressive inherited disorder. While uncommon genetic alterations were uncovered, the children’s symptoms and the clinical findings were in line with typical XLH complications.
The study, “Novel variants and uncommon cases among southern Chinese children with X-linked hypophosphatemia,” was published in the Journal of Endocrinological Investigation.
About 600 XLH-causing mutations have been reported to date. Collectively, they are associated with the excessive secretion of a hormone called FGF23, which suppresses the renal reabsorption of phosphate and the production of vitamin D — both crucial for bone growth and bone remodeling. Such suppression leads to hypophosphatemia, or low blood levels of phosphate, and impaired bone mineralization.
Here, researchers in China determined the sequence of the PHEX gene in 65 children with XLH from 61 families. The children, 41 girls and 24 boys, were seen at Guangzhou Women and Children’s Medical Center between 2011 and 2019. All were of southern Chinese and Han ethnicity. Their age at diagnosis varied from 1 to 12 years, with a median age of 3.
As typical in XLH, most of the children (72.3%) had slow growth. However, problems with skeletal development — such as leg deformities, lower bone density, and bent long bones — also were common. All participants showed low levels of phosphate in the blood and the majority also had elevated activity of liver enzymes.
Multiple methods were used to search for PHEX mutations. In particular, the scientists employed both genetic sequencing and copy number analysis. DNA sequencing is a standard way to assess small changes in a gene. However, because of the particular molecular mechanics involved, sequencing a gene can miss relatively large changes — for example, the deletion of an entire coding portion, known as an exon. The team found eight children whose gross genetic deletions were missed by sequencing, but caught by copy number analysis.
“This highlights the need to bring copy number analysis into molecular detection of XLH supplementary to traditional methods,” the researchers wrote.
Copy number analysis investigates gains and losses of large chunks of DNA sequence consisting of anywhere from 10,000 to 5 million letters.
In total, 51 different mutations were found in the 65 children. Of these mutations, 23 had been previously reported; the remaining 28 are newly identified.
Interestingly, one previously reported mutation, referred to as c.1601C>T, was identified in five unrelated families. This mutation results in an amino acid change from proline to leucine. The finding suggests that this may be a hotspot, which is an area of DNA that is likely to mutate.
A few uncommon XLH cases were found, including that of identical (monozygotic) twins who both carried the same new mutation with similar symptoms and clinical findings.
Four children, all boys, were found to have mosaicism — when a person has multiple sets of genetically distinct cells in the body. Generally, this happens due to an error in cell division early in life. As the cells divide, those with the mutation will pass it on to new cells, resulting in altered numbers of chromosomes.
Mosaicism also was found in one biological father who did not present XLH symptoms. He had isolated germline mosaicism, which means that the mutation was only present in his reproductive cells, specifically his sperm. According to the scientists, this finding “suggests the parents, especially the fathers, should be involved in genetic testing.”
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