• Test code: 04730
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae GLI3-Related Disorders Test

Test description

This test analyzes the GLI3 gene, which is associated with Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), postaxial polydactyly types A and B (PAP-A)(PAP-B), and preaxial polydactyly type IV (PPD-IV).

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (1 gene)

Alternative tests to consider

The Invitae Craniosynostosis Panel has been designed to provide a broad genetic analysis of this class of disorders and may be considered as an alternative to testing for a specific disorder. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.

  • Greig cephalopolysyndactyly syndrome (GCPS)
    • typical Greig cephalopolysyndactyly syndrome
    • mild Greig cephalopolysyndactyly syndrome
  • Pallister-Hall syndrome (PHS)
    • sub-Pallister-Hall syndrome
  • postaxial polydactyly (PAP)
    • postaxial polydactyly type A (PAP-A)
    • postaxial polydactyly type B (PAP-B)
  • preaxial polydactyly type IV (PPD-IV)

Greig cephalopolysyndactyly syndrome is characterized by hypertelorism, limb anomalies (preaxial and postaxial polydactyly, broad hallux, cutaneous syndactyly), and macrocephaly. Intellectual disability and seizures may also be rare manifestations.

Pallister-Hall syndrome is a multiple congenital anomaly syndrome that is characterized by polydactyly, bifid epiglottis, hypothalamic hamartoma, endocrine manifestations, laryngotracheal cleft, imperforate anus, renal anomalies, seizures, genitourinary anomalies, short limbs, and abnormal lung lobation. The severity of these manifestations can be highly variable.

GLI3 mutations can cause isolated polydactyly—preaxial polydactyly type IV and postaxial polydactyly (PAP) type A or B. In PAP-A, the extra digit is well formed and is usually functional. In PAP-B, the extra digit is not well formed and may occur as a rudimentary skin tag.

Pathogenic variants in GLI3 were detected in approximately 95% of individuals with PHS and in approximately 85% of individuals with GCPS.

GLI3-related syndromes are inherited in an autosomal dominant manner.

Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) exhibit high penetrance with variable expressivity. Polydactyly is believed to exhibit intermediate penetrance.

The prevalence of GLI3-related disorders is unknown, but they are believed to be rare. One author estimates prevalence of GCPS at 1–9 in 1,000,000.

  1. Biesecker, LG. What you can learn from one gene: GLI3. J. Med. Genet. 2006; 43(6):465-9. PMID: 16740916
  2. Johnston, JJ, et al. 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. 2005; 76(4):609-22. PMID: 15739154
  3. Johnston, JJ, et al. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Hum. Mutat. 2010; 31(10):1142-54. PMID: 20672375
  4. Démurger, F, et al. New insights into genotype-phenotype correlation for GLI3 mutations. Eur. J. Hum. Genet. 2015; 23(1):92-102. PMID: 24736735
  5. Johnston, JJ, et al. Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome. Am. J. Med. Genet. A. 2003; 123A(3):236-42. PMID: 14608643
  6. Biesecker, LG. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis. 2008; 3:10. PMID: 18435847
  7. Biesecker, LG. Greig Cephalopolysyndactyly Syndrome. 2001 Jul 09. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301619
  8. Biesecker, LG. Pallister-Hall Syndrome. 2000 May 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301638
  9. Radhakrishna, U, et al. 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. 1999; 65(3):645-55. PMID: 10441570

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).

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. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. 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. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. 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
GLI3 NM_000168.5