• Test code: 72039
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    Saliva and assisted saliva are accepted; DNA is not accepted
  • Sample requirements
  • Request a sample kit

Invitae Hypophosphatemia Panel

Test description

The Invitae Hypophosphatemia Panel analyzes 13 genes which are associated with genetic forms of hypophosphatemia.

Genetic testing for the hypophosphatemia genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

This panel has assay limitations that are different from most of our other diagnostic panels. Please see the Assay section below for more details.

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Primary panel (13 genes)


Gene Condition
ALPL Hypophosphatasia
CLCN5 Dent disease
CYP2R1 Vitamin D hydroxylation deficient rickets
CYP27B1 Vitamin D-dependent rickets
DMP1 Hypophosphatemic rickets
ENPP1 Hypophosphatemic rickets, generalized arterial calcification of infancy type (GACI), and Cole disease
FAH Tyrosinemia type I
FAM20C Raine syndrome
FGF23 Hypophosphatemia, familial tumoral calcinosis
FGFR1 Osteoglophonic dysplasia, Hartsfield syndrome, Kallman syndrome, Craniosynostosis
PHEX Hypophosphatemia
SLC34A3 Hypophosphatemic rickets with hypercalciuria
VDR Vitamin D-dependent rickets

Genetic forms of hypophosphatemia are conditions characterized by excess phosphate excreted in the urine. Phosphate is essential for the normal development of bones and/or teeth. Affected individuals have low levels of blood phosphate and normal to low serum levels of calcium and Vitamin D (PMID: 26051471). Because phosphate is essential for normal bone and teeth formation, low levels cause soft, painful, bendable bones. (PMID: 26051471) The genetic forms of hypophosphatemia are heterogeneous conditions which can manifest as severe infantile onset forms to mild, adult onset (PMID:22167381). There is also intra-familial clinical heterogeneity in family members with the same pathogenic variants (PMID: 29949513). The most common form is X-linked hypophosphatemia (XLH). The clinical presentation of XLH is variable and depends on the age of onset and duration of the hypophosphatemia. In children with XLH, the major clinical findings are progressive bowing of the lower limbs as they begin to walk, disproportionate short stature, fractures, signs of rickets, and characteristic radiographic findings (PMID: 21538511). In adult patients, clinical findings include joint pain and impaired mobility (PMID: 29460029). XLH patients produce excess fibroblast growth factor 23 (FGF23) which leads to the hypophosphatemia and clinical consequences (PMID: 28130634, 21538511, 30664852).

Less common forms of hereditary hypophosphatemia which are FGF23 mediated, include the types associated with FGF23, DMP1 and ENPP1 genes (PMID: 22167381). Forms of hereditary hypophosphatemia which are non-FGF23 mediated include the types associated with the CLCN5 and SLC34A3 genes (PMID: 22167381). The hypercalciuria in addition to the hypophosphatasia in patients with the SLC34A3 autosomal dominant form of hypophosphatemia have similar clinical findings to patients with XLH (PMID: 22167381). Patients with DMP1 pathogenic variants also have similar biochemical findings to patients with XLH but have a characteristic radiological finding of high bone density of the vertebral bodies (PMID: 22167381). Dent disease is a rare X-linked recessive condition characterized by the pathognomonic finding of low molecular weight proteinuria and hypercalciuria in addition to renal calcifications, renal stones, hypophosphatemia and/or chronic kidney disease (PMID: 20946626). Hypophosphatasia associated with the ALPL gene also demonstrates clinical heterogeneity with a prenatal onset, lethal, infantile form to individuals who are not diagnosed until adulthood (PMID: 25731960, 30083035).

The PHEX gene accounts for 80-83% of hypophosphatemia in Italian, Turkish, and Danish cohorts (PMID: 26051471, 29505567, 22695891). The CLCN5 gene accounts for 60% of Dent disease (PMID: 20936522). The clinical sensitivity for the remaining genes is unknown.

Gene Condition Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant
ALPL Hypophosphatasia X X
CLCN5 Dent disease X
CYP2R1 Vitamin D hydroxylation deficient rickets X
CYP27B1 Vitamin D-dependent rickets X
DMP1 Hypophosphatemic rickets X
ENPP1 Hypophosphatemic rickets, generalized arterial calcification of infancy type (GACI), and Cole disease X
FAH Tyrosinemia type I X
FAM20C Raine syndrome X
FGF23 Hypophosphatemia, familial tumoral calcinosis X X
FGFR1 Osteoglophonic dysplasia, Hartsfield syndrome, Kallman syndrome, Craniosynostosis X
PHEX Hypophosphatemia X
SLC34A3 Hypophosphatemic rickets with hypercalciuria X
VDR Vitamin D-dependent rickets X

The prevalence of XLH is estimated to be approximately 4.3/100,000 (PMID: 19095780). Other forms of hypophosphatemia are rare. The prevalence of perinatal and infantile hypophosphatasia associated with the ALPL gene is estimated to be 1/300,000 in France and Northern Europe with much higher prevalence of milder, autosomal dominant forms (PMID: 21488855, 29405932).

This test may be appropriate for patients with:

  • Clinical or radiographic signs of rickets
  • Bowing of lower extremities
  • Musculoskeletal pain, stress fractures and dental abscesses in adults
  • Family history of hypophosphatemia
  • Low serum phosphate and normal to low vitamin D levels (age dependent)
  • Elevation of FGF23 (PMID: 22167381, 22319799)
  1. Capelli S, et al. Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. Bone. 2015; 79:143-9. PMID: 26051471
  2. Carpenter, TO, et al. A clinician's guide to X-linked hypophosphatemia. J. Bone Miner. Res. 2011; 26(7):1381-8. PMID: 21538511
  3. Bacchetta, J, et al. Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting. Metab. Clin. Exp. 2019; :None. PMID: 30664852
  4. Faiyaz-Ul-Haque, M, et al. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR): clinical heterogeneity and long-term efficacious management of eight patients from four unrelated Arab families with a loss of function VDR mutation. J. Pediatr. Endocrinol. Metab. 2018; 31(8):861-868. PMID: 29949513
  5. Chesher, D, et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J. Inherit. Metab. Dis. 2018; 41(5):865-876. PMID: 29460029
  6. Fuente, R, et al. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord. 2017; 18(1):107-115. PMID: 28130634
  7. Carpenter, TO. The expanding family of hypophosphatemic syndromes. J. Bone Miner. Metab. 2012; 30(1):1-9. PMID: 22167381
  8. Devuyst, O, Thakker, RV. Dent's disease. Orphanet J Rare Dis. 2010; 5:28. PMID: 20946626
  9. Whyte, MP, et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015; 75:229-39. PMID: 25731960
  10. Oyachi, M, et al. A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature. Clin Pediatr Endocrinol. 2018; 27(3):179-186. PMID: 30083035
  11. Beck-Nielsen, SS, et al. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 2009; 160(3):491-7. PMID: 19095780
  12. Mornet, E, et al. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann. Hum. Genet. 2011; 75(3):439-45. PMID: 21488855
  13. Mornet, E. Genetics of hypophosphatasia. Arch Pediatr. 2017; 24(5S2):5S51-5S56. PMID: 29405932
  14. Acar, S, et al. Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3. PLoS ONE. 2018; 13(3):e0193388. PMID: 29505567
  15. Beck-Nielsen, SS, et al. Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J. Hum. Genet. 2012; 57(7):453-8. PMID: 22695891
  16. Claverie-Martín, F, et al. Dent's disease: clinical features and molecular basis. Pediatr. Nephrol. 2011; 26(5):693-704. PMID: 20936522
  17. Ruppe, MD. X-Linked Hypophosphatemia. 2012 Feb 09. In: Adam, MP, et al, editors. GeneReviews® (Internet). University of Washington, Seattle. PMID: 22319799

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Based on review of current medical guidelines and peer-reviewed publications, our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. Any variants that fall outside these regions are not analyzed unless otherwise noted. Any specific limitations in the analysis of these genes are also listed in the table below.

We use our Boosted Exome assay to analyze the genes included in this panel. To ensure high sensitivity and specificity of calls, the exome is sequenced to an average depth of 150x, with all positions covered to a minimum depth of 20x unless otherwise noted. Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants and insertions and deletions <15bp in length. Sensitivity to detect insertions and deletions larger than 15bp but smaller than a full exon may be marginally reduced. This assay is not intended to detect indels >50 bp. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. The Invitae Boosted Exome includes detection of multi-exon-level copy number variants for clinically-relevant genes, although the resolution for detectable CNV lengths varies among genes due to sequence and coverage properties, and can also be influenced by DNA quality. The assay is not intended to detect variants in mitochondrial DNA. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALPL* NM_000478.5
CLCN5 NM_000084.4
CYP27B1 NM_000785.3
CYP2R1 NM_024514.4
DMP1 NM_004407.3
ENPP1* NM_006208.2
FAH NM_000137.2
FAM20C NM_020223.3
FGF23 NM_020638.2
FGFR1 NM_023110.2
PHEX* NM_000444.5
SLC34A3 NM_080877.2
VDR NM_001017535.1

ALPL: Deletion/duplication analysis is not offered for exon 2.
ENPP1: Deletion/duplication and sequencing analysis is not offered for exon 1 or 16.
PHEX: Analysis includes the NM_000444.5:c.*231A>G variant.