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Hyperphosphatasia with Intellectual Disability via the PIGO Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
PIGO 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4211PIGO81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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


Genetic Counselors


  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

Hyperphosphatasia with mental retardation syndrome-2 or Mabry syndrome (HPRMS2) is a neurological condition characterized by developmental delay and seizures. Psychomotor delay is first noticed around 6 months; patients are hypotonic and motor milestones are delayed. Physical features include a broad nasal bridge, tented lip, and hypoplasia of the fingers and or/nails (Kuki et al. 2013, Nakamura et al. 2014). Seizure onset occurs between 1 and 2 years of age, with most patients experiencing refractory tonic-clonic seizures. There has been a report that patients with PIGO variants may respond well to pyridoxine for seizure control (Kuki et al. 2013). EEG reveals slow waves and multifocal spikes (Krawitz et al. 2012; Kuki et al. 2013). MRI is variable with some patients showing hypomyelination and cerebellar atrophy (Kuki et al. 2013). HPRMS2 patients are severely intellectually disabled and do not acquire meaningful speech.

Biochemical indications of HPRMS2 include elevated levels of serum alkaline phosphatase (ALP) and reduced levels of GPI-anchored proteins on the surface of blood granulocytes as assayed via flow cytometry (Kuki et al. 2013).


HPRMS2 is caused by variants in the PIGO gene and is inherited in an autosomal recessive manner. Pathogenic missense, nonsense, splice site, and frameshift variants in PIGO have been reported (Krawitz et al. 2012; Kuki et al. 2013; Nakamura et al. 2014).

GPIs (glycosylphosphatidylinositol) are glycolipids that are covalently attached to the C-terminus of select proteins and anchor the proteins to the cell surface. Mutations in genes that are part of the GPI-anchor-synthesis pathway result in an array of clinical phenotypes, which are considered to be a subclass of congenital disorders of glycosylation. The PIGO gene encodes GPI ethanolamine phosphate transferase 3, which is required for GPI biosynthesis (Hong et al. 2000). Variants in PIGO lead to defects in GPI biosynthesis, decreased expression of proteins on the cell-surface, and elevated serum levels of alkaline phosphatase (hyperphosphatasia).

Clinical Sensitivity - Sequencing with CNV PG-Select

In a study of 11 families with elevated alkaline phosphatase levels who tested negative for variants in the PIGV gene, 1 family was found to be compound heterozygous for pathogenic PIGO variants (9%)(Krawitz et al. 2012).

Testing Strategy

This test provides full coverage of all coding exons of the PIGO gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

PIGO sequencing should be considered in patients with elevated serum alkaline phosphatase levels and symptoms of HPMRS2 or Mabry disease. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PIGO.


Official Gene Symbol OMIM ID
PIGO 614730
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hyperphosphatasia with mental retardation syndrome 2 AR 614749


  • Hong Y, Maeda Y, Watanabe R, Inoue N, Ohishi K, Kinoshita T. 2000. Requirement of PIG-F and PIG-O for Transferring Phosphoethanolamine to the Third Mannose in Glycosylphosphatidylinositol. Journal of Biological Chemistry 275: 20911–20919. PubMed ID: 10781593
  • Krawitz PM, Murakami Y, Hecht J, Krüger U, Holder SE, Mortier GR, Delle Chiaie B, Baere E De, Thompson MD, Roscioli T, Kielbasa S, Kinoshita T, Mundlos S, Hecht J, Robinson PN, Horn D. 2012. Mutations in PIGO, a Member of the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation. The American Journal of Human Genetics 91: 146–151. PubMed ID: 23561847
  • Kuki I, Takahashi Y, Okazaki S, Kawawaki H, Ehara E, Inoue N, Kinoshita T, Murakami Y. 2013. Vitamin B6-responsive epilepsy due to inherited GPI deficiency. Neurology 81: 1467–1469. PubMed ID: 24049131
  • Nakamura K, Osaka H, Murakami Y, Anzai R, Nishiyama K, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Kinoshita T, Matsumoto N, Saitsu H. 2014. PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels. Epilepsia 55: e13–e17. PubMed ID: 24417746


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

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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