First case of preimplantation genetic testing of X-linked dominantly inherited hypophosphatemia family lines using next-generation sequencing technology.

Background: A 30-year-old female was prenatally diagnosed with X-linked hypophosphatemia (XLH) due to a nonsense variant in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene.

Methods: Using the coding region of the PHEX gene as the target region, multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) were performed, and615 informative single-nucleotide polymorphism (SNP) loci were selected as genetic linkage markers within 1 Mb on both sides of the pathogenic variant. After whole-genome amplification of trophoblast cells via biopsy, Sanger sequencing, NGS-based SNP linkage analysis, and low sequencing depth copy number variation (CNV) analysis were used to directly detect the pathogenic PHEX gene variant, identify the high-risk chromosome and screen for aneuploidy, respectively.

Results: Embryos E2 and E4 are both euploid and have a wild-type PHEX status. Embryos E12, E8 and E7, which are three euploid embryos, each carry the single heterozygous pathogenic PHEX gene variant. Embryo E13 had an abnormal X chromosome, so SNP detection upstream and downstream of the gene revealed abnormalities. Embryos E4 was selected for frozen-thawed embryo transfer, and at mid-pregnancy, invasive prenatal diagnosis revealed that the fetus was not a carrier of the PHEX pathogenic gene variant or chromosomal abnormality, resulting in the full-term delivery of a healthy baby girl.

Conclusions: This is the first report of the successful delivery of an infant with PHEX-related XLH detected by PGT-M. The successful utilization of PGT-M in the family demonstrates its potential as a strategy for assisted reproduction and genetic counselingto manage the inheritance of XLH.