GLI3-Related Disorders via the GLI3 Gene

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).

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.

This test will detect causative mutations in about 70% of GCPS patients (Biesecker 2009), and about 95% of PSH patients (Biesecker 2012).

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).