Identification of a Novel Homozygous Missense Mutation and a Heterozygous Deletion in an Infant with Nephrocalcinosis, Failure to Thrive, and Hypercalcemia.

Renal phosphate transporters NaPi-IIa () and NaPi-IIc () play a crucial role in phosphate reabsorption in the proximal tubule. Biallelic loss-of-function variants in and cause two rare phosphate-wasting tubulopathies: idiopathic infantile hypercalcemia (IIH) and hereditary hypophosphatemic rickets with hypercalciuria, respectively. The phenotypes associated with these diseases are highly variable and sometimes overlap. Here, we report a rare case of a six-month-old girl of consanguineous parents with symptoms related to these diseases, including failure to thrive, nephrocalcinosis, hypercalcemia, hypophosphatemia with low TRP, elevated levels of 1,25-(OH)D, and suppressed PTH. An exome sequencing analysis was carried out to determine the genetic variants associated with her disease. Bioinformatics tools were used to assess variant pathogenicity. We identify a novel homozygous mutation in the gene, c.1361C>T; p.(T454M), and a previously described heterozygous 101 bp deletion. Mutation p.(T454M) affects transmembrane domain 5 of the NaPi-IIa protein, which is involved in substrate binding, probably impairing phosphate transport. Our results suggest the diagnosis of IIH type 2 in our patient and highlight the importance of exome analysis in diagnosing these tubulopathies. We suggest that the coexistent heterozygous deletion could increase the risk of renal calcifications and the severity of other symptoms.