Characterization and Analysis of PHEX Variants in Patients With Hypophosphatemia in Argentina

Confirming the underlying molecular etiology of hereditary hypophosphatemia (HH) to provide recurrence risk counseling is highly important. Our aims were to describe the detected variants and their distribution across Argentina and to contrast them with published data. Patients with HH prospectively referred to a hypophosphatemia program for genetic testing were included. Saliva samples were evaluated by next-generation sequencing with a panel of 13 genes associated with HH. In patients with no variants detected in the HH rickets related gene panel, multiplex ligation-dependent probe amplification was performed for the PHEX gene. Cascade genetic testing was recommended for at-risk relatives of index cases (IC). One hundred and sixty participants were enrolled, including 129 ICs with suspected HH (80.62%). Among them, 114 had a positive molecular test (88.37%); 93% were variations in the PHEX gene, predominantly single-nucleotide variants. Distribution of variant types was consistent with international databases. In our sample, 12% of subjects had undetectable variants in the gene panel, highlighting the importance of complete genome sequencing. Ours is the first study in Latin America to analyze PHEX variants, which is considered crucial for the generation of regional evidence to understand the genetic variability of HH and for leading specific targeted treatment.