GALNT3-Related Disorders via the GALNT3 Gene

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) and Hyperphosphatemic Hyperostosis Syndrome (HHS) are rare, allelic disorders associated with defects in the GALNT3 gene (Frishberg et al. 2005; Rafaelsen et al. 2014). HFTC patients develop periarticular and other ectopic calcifications that can be debilitating. These calcified masses often develop in areas around the hips, elbows, shoulders and knees, although they can develop in other locations. Surgical removal of the masses may be the only viable treatment. These patients may also develop secondary skin and bone infections, painful skin ulcerations, scarring and incapacitating mutilation. Dental abnormalities are also occasionally reported (Topaz et al. 2004; Ichikawa et al. 2005; Campagnoli et al. 2006; Rafaelsen et al. 2014). In contrast, HHS patients do not develop such calcifications, and skin findings are rarely reported in these individuals. Clinically, HHS patients present with recurrent, transient painful swelling of long bones, which may be mistaken for osteosarcoma or other bone malignancies. These patients have been found to have periosteal reactions, diaphysitis, and cortical hyperostosis upon radiological exam (Frishberg et al. 2005).

Although the clinical manifestations are different, the biochemical hallmarks of HFTC and HHS are quite similar. These patients present with persistent hyperphosphatemia with normal serum calcium levels, normal or only slightly elevated levels of 1,25-dihydroxyvitamin D and low or low normal parathyroid hormone levels (Joseph et al. 2010).

Some patients have presented with a combined HFTC + HHS phenotype. In addition, the same GALNT3 variant(s) may lead to HHS in one family member, but HFTC in another (Topaz et al. 2004; Frishberg et al. 2005). Onset of these disorders ranges from childhood to adulthood (Rafaelsen et al. 2014).

Both HFTC and HHS are autosomal recessive disorders. Pathogenic variants in the GALNT3 gene are the most common cause of HFTC and HHS, although variants in the FGF23 and KL genes are also associated with HFTC (Rafaelsen et al. 2014). To date, nearly 30 different causative variants have been reported in the GALNT3 gene. The majority of reported variants are nonsense, splicing or missense variants, although a few small deletions or insertions have also been reported (Human Gene Mutation Database). The variants are spread throughout the gene, and no variants have been reported to be common across multiple ethnic groups.

The GALNT3 gene encodes the UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3) enzyme. This enzyme is required for the glycosylation of the protein fibroblast growth factor 23 (FGF23), which is involved in regulating phosphate levels. Pathogenic variants that lead to defective GalNAc-T3 are thought to prevent the glycosylation of FGF23, thereby allowing its breakdown and inactivation (Garringer et al. 2006; Rafaelsen et al. 2014).

Clinical sensitivity of this test is expected to be high as, to date, all reported patients have been found to be homozygous or compound heterozygous for two pathogenic variants detectable via direct sequencing, suggesting a clinical sensitivity near 100% (Finer et al. 2014; Rafaelsen et al. 2014; Demellawy et al. 2015; Masi et al. 2015; Viera et al. 2015).

This test provides full coverage of all coding exons of the GALNT3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.