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. Greig Cephalopolysyndactyly Syndrome. 2001 Jul 09. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301619
  2. Biesecker, LG. Pallister-Hall Syndrome. 2000 May 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301638
  3. Biesecker, LG. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis. 2008; 3:10. PMID: 18435847
  4. Biesecker, LG. What you can learn from one gene: GLI3. J. Med. Genet. 2006; 43(6):465-9. PMID: 16740916
  5. Démurger, F, et al. New insights into genotype-phenotype correlation for GLI3 mutations. Eur. J. Hum. Genet. 2015; 23(1):92-102. PMID: 24736735
  6. 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
  7. Johnston, JJ, et al. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Hum. Mutat. 2010; 31(10):1142-54. PMID: 20672375
  8. 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
  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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GLI3 NM_000168.5