Hypophosphatemic Rickets with Hypercalciuria via the SLC34A3 Gene

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by hypophosphatemia (secondary to renal phosphate wasting), hypercalciuria, rickets, limb deformities, muscle weakness, and bone pain (Bergwitz et al. 2006. PubMed ID: 16358214; Lorenz-Depiereux et al. 2006. PubMed ID: 16358215). Compared with other types of hypophosphatemic rickets, patients with HHRH present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. Age of onset is in infancy or early childhood. Of note, familial carriers who are heterozygous for a single pathogenic SLC34A3 variant frequently showed hypercalciuria with mild hypophosphatemia and/or increased serum 1,25-dihydroxyvitamin D3, but no bone disease or rickets, suggesting a milder phenotype of autosomal dominant inheritance in some patients (Bergwitz et al. 2006. PubMed ID: 16358214; Dasgupta et al. 2014. PubMed ID: 24700880).

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder caused by defects in the SLC34A3 gene (Bergwitz et al. 2006. PubMed ID: 16358214; Lorenz-Depiereux et al. 2006. PubMed ID: 16358215). As mentioned above, however, familial carriers frequently show a milder phenotype. The SLC34A3 gene (12 coding exons) encodes the renal sodium-phosphate cotransporter NaPi-IIc, which plays a key role in the regulation of phosphate homeostasis. To date, documented genetic defects of SLC34A3 include both missense and truncating variants (splicing variants and small indels, mostly frameshift) (Human Gene Mutation Database). Large deletions have been reported, but appear to be rare.

The pathogenic variant detection rate in the SLC34A3 gene in a large cohort of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is unavailable because each individual study only reported a single family or limited number of cases (Human Gene Mutation Database).

In an international cohort comprising 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16), Halbritter et al. detected likely (or suspected) causative variants in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases (Halbritter et al. 2015. PubMed ID: 25296721). One family (0.37%) was found to have two novel heterozygous missense variants in SLC34A3.

In another international pediatric cohort comprising 143 individuals under 18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20), Braun et al. detected likely (or suspected) causative variants in 14 of the same set of 30 known nephrolithiasis/nephrocalcinosis genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals (Braun et al. 2016. PubMed ID: 26787776). No pathogenic variants were found in SLC34A3.

Large deletions have been reported involving SLC34A3, but appear to be rare (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SLC34A3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).