Inherited Glycosylphosphatidylinositol Biosynthesis Defects (IGDs) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
12645 GPAA1 81479,81479 Order Options and Pricing
PGAP1 81479,81479
PGAP2 81479,81479
PGAP3 81479,81479
PIGA 81479,81479
PIGB 81479,81479
PIGC 81479,81479
PIGG 81479,81479
PIGH 81479,81479
PIGL 81479,81479
PIGM 81479,81479
PIGN 81479,81479
PIGO 81479,81479
PIGP 81479,81479
PIGQ 81479,81479
PIGS 81479,81479
PIGT 81479,81479
PIGU 81479,81479
PIGV 81479,81479
PIGW 81479,81479
PIGY 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
12645Genes x (21)81479 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.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Inherited glycosylphosphatidylinositol (GPI) biosynthesis defects (IGDs) are a group of related conditions that are caused by improperly synthesized GPI anchors and include disorders such as Mabry syndrome, CHIME, hyperphosphatasia with mental retardation syndrome, and multiple congenital anomalies-hypotonia-seizures syndrome. Pathogenic variants within genes responsible for GPI-anchor biosynthesis result in a wide spectrum of clinical phenotypes that can range from mild to severe depending on where the variant occurs in the pathway and the degree to which protein function is impacted (Bellai-Dussault et al. 2019. PubMed ID: 30054924; Ng and Freeze. 2015. PubMed ID: 25164783).

IGDs typically present within the neonatal period and are a rare cause of developmental delay. The incidence of IGDs within a study of 4,000 trios consisting of a proband with a developmental disorder and their unaffected parents was ~0.15% (Pagnamenta et al. 2017. PubMed ID: 28327575). The main/uniting clinical features of IGDs include global developmental delay, intellectual disability, seizures, and hypotonia. Other common features of IGDs can include microcephaly, facial dysmorphism (variable), hyperphoshatasia (variable) and neurological anomalies (tremors, spasticity, rigidity, ataxia, and dystonia). Minor clinical features of IGDs, which are typically associated with specific gene defects, can include the following: hearing impairment, ophthalmological (colobomas, cortical visual impairment, strabismus, nystagmus), cardiac (ventricular septum defects, atrial septal defect, patent ductus arteriousis), urological/renal (ureteral dilation, hydronephrosis, and dysplastic kidney), gastrointestinal (GERD, Hirshsprung disease, anal atresia, anal stenosis, and anteriorly placed anus), nephrocalcinosis, dental (widely spaced teeth, microdontia, abnormal shape, absence of teeth), hand and foot (clinodactyly, oligodactyly, brachytelephalangy, nail hypoplasia) skeletal (scoliosis, osteoporosis, delayed bone age, hip dysplasia), brain (thin corpus callosum, cerebellar and cerebral atrophy, white matter loss, delayed myelination), and polyhydramnios.

Because IGDs are rare with clinical features that are highly variable and often overlap with other developmental disorders, genetic testing is increasingly recognized as an important diagnostic tool (Freeze et al. 2014. PubMed ID: 24507773). Genetic testing can also yield recurrence risks and provide benefit to families for purposes of reproductive planning. Although therapies for IGDs are currently limited, genetic testing and diagnosis may also help to inform treatment options. For example, treatment with sodium phenylbutyrate led to improvement or remission of seizures in individuals with PIGM promoter variants (Almeida et al. 2007. PubMed ID: 17442906; Pode-Shakked et al. 2019. PubMed ID: 31445883). Additionally, a patient with PIGO variants experienced remission of seizures when treated with pyridoxine (B6) (Kuki et al. 2013. PubMed ID: 24049131).

Genetics

IGDs are mostly inherited in an autosomal recessive manner. One exception to this are IGDs related to variants in PIGA which are inherited through an X-linked recessive manner. Males with pathogenic variants in PIGA present with a severe phenotype while female carriers are unaffected (Johnston et al. 2012. PubMed ID: 22305531; Belet et al. 2014. PubMed ID: 24357517). Somatic variants in PIGA have also been reported in individuals with paroxysmal nocturnal hemoglobinuria (Savoia et al. 1996. PubMed ID: 8557259; Bessler and Hiken. 2008. PubMed ID: 19074066).

The majority of IGD causing-variants are missense, nonsense, and frameshift variants. Splicing variants as well as partial/whole gene duplications and deletions have been reported in a few cases (PIGL: Ng et al. 2012. PubMed ID: 22444671; PIGG: Makrythanasis et al. 2016. PubMed ID: 26996948). De novo variants in IGDs have not been reported.

The GPI anchor is a highly conserved post-translational modification used by over 150 proteins to appropriately traffic within the cell, attach to the outer leaflet of the cell membrane, and partake in a vast array of essential cellular functions including enzymatic activity, cell-cell adhesion, cellular recognition, signaling, transport, and migration. GPI-anchor biosynthesis occurs through a series of steps that can be broken down into three stages. The entire process requires over 30 proteins and takes place in both the endoplasmic reticulum (ER) and the golgi. The first stage begins on the cytoplasmic side of the ER with a complex of proteins (PIGA, PIGC, PIGH, PIGP, PIGQ and PIGY) initiating the attachment of a carbohydrate moiety to a lipid base. After a processing step by PIGL, the GPI-anchor is flipped to the inside of ER. Additional carbohydrate moieties are added and modified through a series of enzymatic steps by PIGW, PIGM, PIGX, PIGV, PIGB, PIGN, PIGF, PIGO, and PIGG. During the second stage of the GPI-anchor biosynthesis pathway, the GPI-anchor is transferred to the C-terminus of a protein by a second complex of proteins (PIGT, PIGK, PIGS, PIGU, and GPAA1). Once the GPI-anchor is attached, the third step of synthesis begins and involves further modification of the GPI-anchor, by PGAP1 and PGAP5. At this point, the protein-GPI-anchor complex is transfered to the lumen of the golgi where further processing is carried out by PGAP3 and PGAP2. After processing is complete, GPI-anchored proteins are sorted into distinct vesicles and are then delivered to the cellular membrane where they typically associate with microdomains or lipid rafts (Zurzolo and Simons. 2016. PubMed ID: 26706096). For comprehensive reviews of this process, see Kinoshita and Fujita. 2016. PubMed ID: 26563290, and Maeda and Kinoshita. 2011. PubMed ID: 21658410.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

IGDs are rare and many clinical features have variable severity and overlap with other developmental disorders, making it difficult to estimate the clinical sensitivity of this test. Measurement of alkaline phosphatase (AP), a GPI-anchored protein, through blood testing has helped to diagnose certain IGDs that result in elevation of AP (hyperphosphatasia) (Mabry et al. 1970. PubMed ID: 5465362; Chiyonobu et al. 2014. PubMed ID: 24367057). However, hyperphosphatasia is not a hallmark feature of all IGDs and therefore not an ideal test for clinical classification. Additionally, fluorescence-activated cell sorting (FACS) has been used clinically to measure cell surface expression of GPI-anchored proteins through labelling of CD59, CD55, and the GPI-anchor (FLAER) in individuals with IGDs (Knaus et al. 2018. PubMed ID: 29310717; Sutherland et al. 2007. PubMed ID: 17285629). Facial gestalt software may also help to diagnoses individuals with IGDs (Knaus et al. 2018. PubMed ID: 29310717).

Analytical sensitivity should be high as all reported pathogenic variants are detectable by sequencing.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes 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 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).

Indications for Test

Candidates for this test are individuals showing clinical features consistent with IGDs.

Genes

Official Gene Symbol OMIM ID
GPAA1 603048
PGAP1 611655
PGAP2 615187
PGAP3 611801
PIGA 311770
PIGB 604122
PIGC 601730
PIGG 616918
PIGH 600154
PIGL 605947
PIGM 610273
PIGN 606097
PIGO 614730
PIGP 605938
PIGQ 605754
PIGS 610271
PIGT 610272
PIGU 608528
PIGV 610274
PIGW 610275
PIGY 610662
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
PGxome®
Hyperphosphatasia with Intellectual Disability via the PIGO Gene
Intellectual Disability via the PIGG Gene
Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 via the PIGA Gene
Syndromic Intellectual Disability via the PIGY Gene

Citations

  • Almeida et al. 2007. PubMed ID: 17442906
  • Belet et al. 2014. PubMed ID: 24357517
  • Bellai-Dussault et al. 2019. PubMed ID: 30054924
  • Bessler and Hiken. 2008. PubMed ID: 19074066
  • Chiyonobu et al. 2014. PubMed ID: 24367057
  • Freeze et al. 2014. PubMed ID: 24507773
  • Johnston et al. 2012. PubMed ID: 22305531
  • Kinoshita and Fujita. 2016. PubMed ID: 26563290
  • Knaus et al. 2018. PubMed ID: 29310717
  • Kuki et al. 2013. PubMed ID: 24049131
  • Mabry et al. 1970. PubMed ID: 5465362
  • Maeda and Kinoshita. 2011. PubMed ID: 21658410
  • Makrythanasis et al. 2016. PubMed ID: 26996948
  • Ng and Freeze. 2015. PubMed ID: 25164783
  • Ng et al. 2012. PubMed ID: 22444671
  • Pagnamenta et al. 2017. PubMed ID: 28327575
  • Pode-Shakked et al. 2019. PubMed ID: 31445883
  • Savoia et al. 1996. PubMed ID: 8557259
  • Sutherland et al. 2007. PubMed ID: 17285629
  • Zurzolo and Simons. 2016. PubMed ID: 26706096

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

  • 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.

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

Specimen Requirements and Shipping Details

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