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  • Test code: 72038
  • 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
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Invitae X-Linked Hypophosphatemia Test

Test description

The Invitae X-Linked Hypophosphatemia Test analyzes the PHEX gene, which is associated with a genetic form of hypophosphatemia.

Genetic testing of this gene 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 test 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 (1 gene)

PHEX

X-linked hypophosphatemic rickets is a condition characterized by delayed growth, bone pain, bone deformities, loss of teeth and dental abscesses (PMID: 21538511). The clinical presentation of XLH is variable and depends on the age of onset and duration of the hypophosphatemia. In children, 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. In adult patients, clinical findings include joint pain and impaired mobility. In one cohort of patients over 40 years of age, joint replacement and laminectomy were common (PMID: 29460029). Adults also had dental disease (63%), nephrocalcinosis (42%) and hearing impairment (14%) (PMID: 29460029). Affected individuals have low levels of blood phosphate and normal serum levels of calcium and Vitamin D. Because phosphate is essential for normal bone and teeth formation, low levels cause soft, painful, bendable bones. XLH patients produce excess fibroblast growth factor 23 (FGF23) which leads to the hypophosphatasia and clinical consequences (PMID: 28130634, 21538511).

The PHEX gene accounts for 80-83% of hypophosphatemia in Italian, Turkish, and Danish cohorts (PMID: 26051471, 29505567, 22695891).

XLH is an X-linked dominant disorder which means that males and females are similarly affected.

  • Affected males may have mothers who are hemizygous for the PHEX gene or they may have a de novo pathogenic variant. An affected male passes the pathogenic variant to all of his daughters and none of his sons.
  • Affected males can not have affected fathers.
  • Affected females may have inherited the PHEX pathogenic variant from either parent or the pathogenic variant may be de novo or the result of germline mosaicism. An affected female has a 50% chance of passing the pathogenic variant to her offspring.
  • If there is a positive family history of XLH, the mother of the affected male is an obligate carrier of the condition.

There are mildly affected individuals, so molecular testing for the PHEX gene is indicated for at-risk family members.

The prevalence of XLH is estimated to be approximately 4.3 in 100,000 (PMID: 19095780)

Clinical findings:

  • Clinical signs of rickets/radiographic signs of rickets
  • Bowing of lower extremities
  • Musculoskeletal pain, stress fractures and dental abscesses in adults
  • Family history of XLH

Biochemical findings:

  • Low serum phosphate (age-dependent) (PMID: 22319799)

  1. Carpenter, TO, et al. A clinician's guide to X-linked hypophosphatemia. J. Bone Miner. Res. 2011; 26(7):1381-8. PMID: 21538511
  2. 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
  3. Fuente, R, et al. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord. 2017; 18(1):107-115. PMID: 28130634
  4. 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
  5. 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
  6. 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
  7. Ruppe, MD. X-Linked Hypophosphatemia. 2012 Feb 09. In: Adam, MP, et al, editors. GeneReviews® (Internet). University of Washington, Seattle. PMID: 22319799
  8. Bitzan, M, Goodyer, PR. Hypophosphatemic Rickets. Pediatr. Clin. North Am. 2019; 66(1):179-207. PMID: 30454743
  9. Cagnoli, M. Spontaneous growth and effect of early therapy with calcitriol and phosphate in X-linked hypophosphatemic rickets. Pediatr Endocrinol Rev. 2017; 15(Suppl 1):119-122 PMID: 29292875
  10. Lyseng-Williamson, KA. Burosumab in X-linked hypophosphatemia: a profile of its use in the USA. Drugs Ther Perspect. 2018; 34(11):497-506. PMID: 30459508
  11. Capelli S, et al. Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. Bone. 2015; 79:143-9. PMID: 26051471

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
PHEX* NM_000444.5

PHEX: Analysis includes the NM_000444.5:c.*231A>G variant.