Identification of a Novel Homozygous SLC34A1 Missense Mutation and a Heterozygous SLC34A3 Deletion in an Infant with Nephrocalcinosis, Failure to Thrive, and Hypercalcemia

Renal phosphate transporters NaPi-IIa (<i>SLC34A1</i>) and NaPi-IIc (<i>SLC34A3</i>) play a crucial role in phosphate reabsorption in the proximal tubule. Biallelic loss-of-function variants in <i>SLC34A1</i> and <i>SLC34A3</i> 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)₂D₃, 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 <i>SLC34A1</i> gene, c.1361C>T; p.(T454M), and a previously described heterozygous <i>SLC34A3</i> 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 <i>SLC34A3</i> deletion could increase the risk of renal calcifications and the severity of other symptoms.