Unusual <i>PHEX</i> variants implicate uncommon genetic mechanisms for X-linked hypophosphatemic rickets

X-linked hypophosphatemic rickets (XLH), the most common form of hereditary rickets, is characterized by renal phosphate wasting and abnormal vitamin D metabolism due to elevated circulating levels of the phosphatonin fibroblast growth factor 23 (FGF23). Dominant inactivating variants of the phosphate regulating endopeptidase homolog, X-linked (<i>PHEX</i>), gene are present in patients with XLH, and more than half of affected patients carry de novo variants. We report on 3 families in whom affected members had highly unusual <i>PHEX</i> pathogenic variants. In 1 family we identified a previously described deep intronic <i>PHEX</i> variant (c.1768 + 173A>G) in the proband and her affected son. This variant is also near a previously reported PHEX variant (c.1768 + 177_1768 + 180dupGTAA) and is predicted to affect splicing by SpliceAI (delta score: 0.95) through creation of a new donor splice site. In a second proband we identified 2 pathogenic de novo and novel <i>PHEX</i> variants, c.2083delT (p.Ser695Profs*45) and c.2085delC (p.Tyr696Thrfs*44), that were present on different alleles, consistent with mosaicism for 3 <i>PHEX</i> alleles. The third proband also carried 2 <i>PHEX</i> variants (c.755 T>C [p.Phe252Ser] and c.759G>A [p.Met253Ile]), but in this case both variants were present on the same <i>PHEX</i> allele. These studies expand the molecular catalog of pathogenic <i>PHEX</i> variants in XLH and emphasize the importance of deep intronic sequencing and comprehensive family studies. Conventional approaches to genetic diagnosis may not be adequate to identify or characterize the disease-causing variants in the <i>PHEX</i> gene in some patients with likely XLH.