Intragenic duplication of PHEX in a girl with X-linked hypophosphatemia: a case report with review of literature.

Over 70 intragenic copy-number variations (CNVs) of PHEX have been identified in patients with X-linked hypophosphatemia (XLH). However, the underlying mechanism of these CNVs has been poorly investigated. Furthermore, although PHEX undergoes X chromosome inactivation (XCI), the association between XLH in women with heterozygous PHEX variants and skewed XCI remains unknown. In this study, we determined the precise genomic structure and the XCI status of a girl with XLH who showed short stature and bowing of the legs at 2 years old. Laboratory tests revealed low levels of serum phosphate and elevated levels of alkaline phosphatase and fibroblast growth factor 23. Multiplex ligation-dependent probe amplification and targeted long-read sequencing revealed that she carried a 24.6-kb intragenic duplication of PHEX. The duplication was tandemly aligned in a head-to-tail orientation. The duplication breakpoints shared a 2-bp microhomology, indicating that this CNV resulted from a replication-based error. Trio sequencing results showed that the duplication was a de novo CNV that occurred on the paternally-derived allele. DNA methylation analysis demonstrated random XCI. A literature review of 12 previously reported cases of intragenic CNVs of PHEX revealed that the deletions/duplications can be ascribed to replication-based errors. Our findings and those of previous studies indicate that XLH-causative CNVs in PHEX predominantly arise from replication-based errors. Thus, the genomic region surrounding PHEX may be vulnerable to replication-based errors during gametogenesis or early embryogenesis. Our study provides supporting evidence that heterozygous PHEX variants can lead to XLH in women with random XCI.