GLI3-Related Disorders via the GLI3 Gene
Summary and Pricing
Test Method
Exome Sequencing with CNV DetectionTest Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
---|---|---|---|---|---|
8103 | GLI3 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.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.
Clinical Features and Genetics
Clinical Features
Greig Cephalopolysyndactyly Syndrome (GCPS) is a clinically heterogeneous disorder that is characterized by craniofacial and digital malformations. The clinical diagnosis of GCPS is based on the presence of preaxial polydactyly, syndactyly, macrocephaly, and ocular hypertelorism (Johnston et al. Hum Mutat 31:1142-54, 2010). Additional features include prominent forehead, seizures, hydrocephalus, developmental delay, learning difficulties and postaxial polydactyly. For more information see Biesecker GeneReviews 2009 (http://www.geneclinics.org/).
Pallister-Hall Syndrome (PHS) characterized by postaxial polydactyly and hypothalamic hamartoma (Johnston, 2010). Additional features include gelastic seizures, small nails, imperforate anus, bifid epiglottis and laryngotracheal clefts. PHS patients may have pituitary insufficiency which can result in death from adrenal insufficiency. Symptoms are variable in appearance and severity. Inter-familial variability has been reported to be much greater than intra-familial variability. For more information see Biesecker GeneReviews 2012 (http://www.geneclinics.org/).
Nonsyndromic polydactyly, including preaxial and postaxial, is characterized by abnormalities in the digits of the hands or feet with no other symptoms or abnormalities that are usually present in GCPS or PHS (Radhakrishna et al. Nat Genet 17:269–71, 1997; Radhakrishna et al. Am J Hum Genet 65:645–55, 1999).
Genetics
GCPS is an autosomal dominant disorder that is caused by loss of function mutations in the GLI3 gene (Vortkamp et al. Nature 352:539-40; 1991; Kalff-Suske et al. Hum Mol Genet 8:1769-77, 1999; Johnston et al. Am J Hum Genet 76: 609-22, 2005). Mutations occur either de novo or are inherited dominantly. The fraction of patients with de novo mutations is unknown. GLI3 is the only gene that has been implicated in GCPS. Causative mutations are located throughout the length of the gene, but especially within the first and last thirds of the gene (Johnston et al. 2005; Johnston, 2010). About 5-10% of GCPS patients have large deletions or translocations involving the GLI3 gene (Johnston et al. Am J Med Genet A 123:236-42, 2003; Biesecker 2009).
PHS is an autosomal dominant disorder that is caused by mutations in the GLI3 gene. These mutations result in a constitutive repressor protein leading to a loss of balance between the activator and repressor forms of the GLI3 protein, which is critical for Sonic Hedgehog (SHH) signaling (Kang et al. Nat Genet 15:266-8, 1997; Johnston, 2005). Mutations either occur de novo or are inherited dominantly. De novo mutations occur in ~ 25 % of patients and are usually associated in a more severe phenotype compared to that of familial cases (Biesecker, 2012). PHS mutations are mostly (possibly even entirely) truncating (nonsense, frameshift, and obvious splicing defects) and are usually located within the middle third of the gene (Johnston, 2005). No large deletions or complex rearrangements have been reported to date. GLI3 is the only gene that has been implicated in PHS.
In addition to GCPS and PHS, heterozygous mutations in the GLI3 gene cause nonsyndromic polydactyly (Radhakrishna 1997; Radhakrishna 1999). GLI3 encodes a zinc finger protein of the GLI family, which has a double role. The GLI3 protein acts as a DNA-binding transcription factor and as a mediator of SHH signaling, which is involved in the regulation of vertebrate organogenesis.
Clinical Sensitivity - Sequencing with CNV PGxome
This test will detect causative mutations in about 70% of GCPS patients (Biesecker 2009), and about 95% of PSH patients (Biesecker 2012).
Testing Strategy
This test provides full coverage of all coding exons of the GLI3 gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).
Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).
Indications for Test
Patients with symptoms consistent with GCPS, PHS or nonsyndromic polydactyly are candidates for this test.
Patients with symptoms consistent with GCPS, PHS or nonsyndromic polydactyly are candidates for this test.
Gene
Official Gene Symbol | OMIM ID |
---|---|
GLI3 | 165240 |
Inheritance | Abbreviation |
---|---|
Autosomal Dominant | AD |
Autosomal Recessive | AR |
X-Linked | XL |
Mitochondrial | MT |
Diseases
Name | Inheritance | OMIM ID |
---|---|---|
Greig Cephalopolysyndactyly Syndrome | AD | 175700 |
Pallister-Hall Syndrome | AD | 146510 |
Polydactyly Preaxial Type 4 | AD | 174700 |
Polydactyly, Postaxial, Type A1 | AD | 174200 |
Citations
- Johnston et al. (2003). "Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome." Am J Med Genet A 123A(3): 236-42. PubMed ID: 14608643
- Johnston et al. (2010). "Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations." Hum Mutat 31: 1142-54. PubMed ID: 20672375
- Johnston et.al. (2005). "Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations." Am J Hum Genet 76(4): 609-22. PubMed ID: 15739154
- Kalff-Suske et.al. (1999). "Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome." Hum Mol Genet 8: 1769-77. PubMed ID: 10441342
- Kang al. (1997). "GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome." Nat Genet 15(3): 266-8. PubMed ID: 9054938
- Leslie G Biesecker. "Greig Cephalopolysyndactyly Syndrome." GeneReviews, 2009. PubMed ID: 20301619
- Leslie G Biesecker. "Pallister-Hall Syndrome." GeneReviews, 2012. PubMed ID: 20301638
- Radhakrishna et al. (1997). "Mutation in GLI3 in postaxial polydactyly type A. Nat Genet 17:269–71". PubMed ID: 9354785
- Radhakrishna et al. (1999). "The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations". Am J Hum Genet 65:645–55. PubMed ID: 10441570
- Vortkamp et al. (1991). "GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families." Nature 352:539-40. PubMed ID: 1650914
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.
- 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
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
ORDER OPTIONS
View Ordering Instructions1) Select Test Type
2) Select Additional Test Options
No Additional Test Options are available for this test.