Hypophosphatasia (HPP) and Inherited Hypophosphatemic Rickets Panel

Hypophosphatasia (HPP) is characterized by defective mineralization of bone and/or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. At least six clinical forms are currently recognized based on age at diagnosis and severity of features, including: (1) perinatal lethal HPP characterized by respiratory insufficiency and hypercalcemia; (2) perinatal benign HPP with prenatal skeletal manifestations that slowly resolve into the milder childhood or adult form; (3) infantile HPP with onset between birth and age six months of rickets; (4) childhood HPP that ranges from low bone mineral density for age with unexplained fractures to rickets; (5) adult HPP characterized by early loss of adult dentition and stress fractures and pseudofractures of the lower extremities in middle age; and (6) odontohypophosphatasia characterized by premature exfoliation of primary teeth and/or severe dental caries as an isolated finding or as part of the above forms of HPP (Mornet and Nunes. 2016. PubMed ID: 20301329). HPP is caused by pathogenic variants in the ALPL gene.

Hypophosphatemic rickets is condition of abnormal phosphate homeostasis characterized by renal phosphate wasting, hypophosphatemia, and rickets/osteomalacia. Patients usually manifest bone deformity such as bowed legs after 2 years old, patients will also develop pain in pelvis and legs with age (Bastepe and Jüppner. 2008. PubMed ID: 18365315).

Autosomal dominant and autosomal recessive Hypophosphatasia are caused by pathogenic variants in the ALPL gene.

X-linked Hypophosphatemic Rickets is mainly caused by deleterious variants in the PHEX gene and rarely caused by deleterious variants in CLCN5 (Hauer et al. 2018. PubMed ID: 29758562).

Autosomal dominant Hypophosphatemic Rickets is caused by pathogenic variants in FGF23 gene.

Autosomal recessive Hypophosphatemic Rickets is currently known to be caused by deleterious variants in the CYP27B1, DMP1, SLC34A3, ENPP1, CYP2R1 (Molin et al. 2017. PubMed ID: 28548312), SLC34A3 (Braun et al. 2016. PubMed ID: 26787776) and VDR (Malloy et al. 2014. PubMed ID: 24246681) genes.

Pathogenic variants in ENPP1 also cause autosomal recessive Arterial calcification, generalized, of infancy, type 1.

Pathogenic variants in FGF23 also cause autosomal recessive Tumoral calcinosis, familial hyperphosphatemic.

Pathogenic variants in the SLC34A1 have also been reported in patients with both autosomal dominant and autosomal recessive hypophosphataemic nephrolithiasis/osteoporosis; hypercalcemia (Braun et al. 2016. PubMed ID: 26787776).

Pathogenic variants in the VDR gene have also been reported in patients with autosomal dominant Osteoporosis, involutional (Mohammadi et al. 2014. PubMed ID: 25364703).

See individual gene test descriptions for information on the molecular biology of each gene product, and spectra of pathogenic variants.

Sequencing of ALPL is predicted to detect pathogenic variants in 95% of cases with severe perinatal and infantile Hypophosphatasia (HPP). In milder forms, the detection rate is difficult to estimate. Overall, ~50% of cases with a clinical diagnosis of HPP have two ALPL pathogenic variants and ~40%-45% have one pathogenic variant. The milder the disease, the higher the proportion in which only one ALPL pathogenic variant is detected (Mornet and Nunes. 2016. PubMed ID: 20301329).

To our knowledge, only a few large deletions involving ALPL have been reported (Mornet and Nunes. 2016. PubMed ID: 20301329). Large deletions account for 2.2% of reported ALPL pathogenic variants in an ALPL mutation database (http://www.sesep.uvsq.fr/03_hypo_mutations.php).

Only a few DMP1 pathogenic variants have been reported: 1 missense, 1 nonsense, 2 splicing, 4 small deletion and one large deletion (Farrow et al. 2009. PubMed ID: 19007919; Human Gene Mutation Database). In one study, a DMP1 pathogenic variant was identified in all three studied families with autosomal recessive hypophosphatemia (Lorenz-Depiereux et al. 2006. PubMed ID: 17033625).

Pathogenic variants in ENPP1 were found in 62 of 92 affected patients who were from 85 unrelated families with clinical diagnosed Spontaneous pathologic arterial calcifications or pseudoxanthoma elasticum (Nitschke et al. 2012. PubMed ID: 22209248). Only one large deletion including exons 24 to 25 of the ENPP1 gene was reported in a patient affected with Autosomal-Recessive Hypophosphatemic Rickets (Lorenz-Depiereux et al. 2010. PubMed ID: 20137773).

CYP27B1 pathogenic variants were reported in 22 patients from 13 Turkish families affected with Vitamin D-Dependent Rickets Type I, and the recurrent variants were c.195 + 2T>G, c.574A>G, and c.590G>A. (Tahir et al. 2016. PubMed ID: 26982175). All reported pathogenic variants were missense, small del/dup, splicing site variants. No large del/dup has been reported (HGMD).

A total of 15 missense pathogenic variants and one large deletion in the FGF23 gene have been reported (HGMD). One large deletion involving FGF23 was reported in a family with three sibs affected with hyperphosphatemia with calcification and tumoral calcinosis, who also carried another FGF23 missense mutation (Shah et al. 2014. PubMed ID: 25378588).

In one study, PHEX pathogenic variants were identified 93 out of 118 probands (79%) (Gaucher et al. 2009. PubMed ID: 19219621). In another study, PHEX pathogenic variants were identified in 20 out of 24 unrelated probands (83%); three of these probands carried a large deletion or duplication detected by MLPA (Beck-Nielsen et al. 2012. PubMed ID: 22695891).

In one study, SLC34A3 pathogenic variants were found in one patient from 268 studied families with Nephrocalcinosis (Halbritter et al. 2015. PubMed ID: 25296721). In another study, SLC34A3 pathogenic variants were found in all 5 studied families with autosomal recessive Hypophosphatemic Rickets with Hypercalciuria (Lorenz-Depiereux et al. 2006. PubMed ID: 16358215).

The homozygous VDR nonsense variant c.885C>A (p.Y295*) was reported in 8 patients from four unrelated southern region Saudi Arabia families (Faiyaz-Ul-Haque et al. 2018. PubMed ID: 29949513). In another study, two different homozygous VDR missense variants were detected in 8 patients from 7 Tunisian families (Ameur et al 2017. PubMed ID: 28013309).

Pathogenic variants in CLCN5 have been mainly reported in patients with X-linked Dent disease. In one study, pathogenic variants were reported in 52% (47/90) of patients with Dent disease (Mansour-Hendili et al. 2015. PubMed ID: 25907713).

In one cohort study, pathogenic variants in SLC34A1 were been reported in 5/143 (3.4%) of patients with Nephrolithiasis or Nephrocalcinosis (Braun et al. 2016. PubMed ID: 26787776).

In one study, rare missense variants in CYP2R1 were identified in 2 of 14 family cases with Vitamin D Deficiency, but no potential CYP2R1 pathogenic variants were found in 27 studied isolated cases with Vitamin D Deficiency (Thacher et al. 2015. PubMed ID: 25942481).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes listed 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).