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