Hypophosphatasia (HPP) and Inherited Hypophosphatemic Rickets Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3251 ALPL 81479,81479 Order Options and Pricing
CLCN5 81479,81479
CYP27B1 81479,81479
CYP2R1 81479,81479
DMP1 81479,81479
ENPP1 81479,81479
FGF23 81404,81479
PHEX 81406,81479
SLC34A1 81479,81479
SLC34A3 81479,81479
VDR 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3251Genes x (11)81479 81404, 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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.

Testing Strategy

This panel provides full 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Indications for Test

Candidates for this test include patients with a clinical presentation of hypophosphatasia, or Inherited Hypophosphatemic Rickets, or individuals with a family history of hypophosphatasia as well as Inherited Hypophosphatemic Rickets.

Genes

Official Gene Symbol OMIM ID
ALPL 171760
CLCN5 300008
CYP27B1 609506
CYP2R1 608713
DMP1 600980
ENPP1 173335
FGF23 605380
PHEX 300550
SLC34A1 182309
SLC34A3 609826
VDR 601769
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Ameur et al 2017. PubMed ID: 28013309
  • Bastepe and J├╝ppner. 2008. PubMed ID: 18365315
  • Beck-Nielsen et al. 2012. PubMed ID: 22695891
  • Braun et al. 2016. PubMed ID: 26787776
  • Faiyaz-Ul-Haque et al. 2018. PubMed ID: 29949513
  • Farrow et al. 2009. PubMed ID: 19007919
  • Gaucher et al. 2009. PubMed ID: 19219621
  • Halbritter et al. 2015. PubMed ID: 25296721
  • Hauer et al. 2018. PubMed ID: 29758562
  • Human Gene Mutation Database (Bio-base).
  • Lorenz-Depiereux et al. 2006. PubMed ID: 16358215
  • Lorenz-Depiereux et al. 2006. PubMed ID: 17033625
  • Lorenz-Depiereux et al. 2010. PubMed ID: 20137773
  • Malloy et al. 2014. PubMed ID: 24246681
  • Mansour-Hendili et al. 2015. PubMed ID: 25907713
  • Mohammadi et al. 2014. PubMed ID: 25364703
  • Molin et al. 2017. PubMed ID: 28548312
  • Mornet and Nunes. 2016. PubMed ID: 20301329
  • Nitschke et al. 2012. PubMed ID: 22209248
  • Shah et al. 2014. PubMed ID: 25378588
  • Tahir et al. 2016. PubMed ID: 26982175
  • Thacher et al. 2015. PubMed ID: 25942481

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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