Greig cephalopolysyndactyly syndrome is characterized by frontal bossing, scaphocephaly, and hypertelorism associated with pre- and postaxial polydactyly and variable syndactyly. The phenotype shows variable expressivity and can also include craniosynostosis. Affected individuals usually have normal psychomotor development (summary ... Greig cephalopolysyndactyly syndrome is characterized by frontal bossing, scaphocephaly, and hypertelorism associated with pre- and postaxial polydactyly and variable syndactyly. The phenotype shows variable expressivity and can also include craniosynostosis. Affected individuals usually have normal psychomotor development (summary by Gorlin et al., 2001).
Greig (1928) described digital malformations and peculiar skull shape in mother and daughter. The mother had syndactyly of both hands. The daughter, of above average intelligence, had polysyndactyly and a peculiar skull shape in the form of expanded ... Greig (1928) described digital malformations and peculiar skull shape in mother and daughter. The mother had syndactyly of both hands. The daughter, of above average intelligence, had polysyndactyly and a peculiar skull shape in the form of expanded cranial vault leading to high forehead and bregma, with no evidence of precocious closure of cranial sutures. The thumbs and great toes had bifid terminal phalanges. Marshall and Smith (1970) reported a family with dominant inheritance of what they termed 'frontodigital syndrome.' Intelligence was normal. Merlob et al. (1981) reported a female infant with postaxial polydactyly of the hands, preaxial polydactyly of the feet, with syndactyly, and craniofacial dysmorphism characterized by frontal bossing. X-ray examination revealed markedly advanced bone age. There was also bilateral hip dislocation. The father of the infant had a high forehead and mild hypertelorism. Fryns et al. (1981) described the disorder in dizygotic 4-month-old twin brothers and their father; the twins had severe affection, the father mild. Chudley and Houston (1982) described the syndrome in 3 generations of a family and perhaps by implication in a fourth. They commented on phenotypic overlap with the acrocallosal syndrome (ACLS; 200990). Baraitser et al. (1983) reported 13 affected persons in 3 kindreds with, curiously, no male-to-male transmission. They also commented on similarity to the acrocallosal syndrome. The main clinical distinction was mental retardation, involving agenesis of the corpus callosum. Legius et al. (1985) proposed that the acrocallosal syndrome is the same as Greig syndrome. Marafie et al. (1996) reported Bedouin father and son with Greig cephalopolysyndactyly syndrome; the son had the rare association of mild mental retardation and dysgenesis of the corpus callosum. They noted that dysgenesis of the corpus callosum with mild mental retardation had been reported in only 1 other patient with GCPS (Hootnick and Holmes, 1972). Baraitser et al. (1983) observed that the facial features of Greig syndrome can be so mild as to be indistinguishable from the normal. Therefore they suggested that type IV preaxial polydactyly, or uncomplicated polysyndactyly (174700), as delineated by Temtamy and McKusick (1978), may be Greig syndrome. The family reported by Ridler et al. (1977) as an example of type II syndactyly (186000) was in fact a family with Greig syndrome, as established by Winter (1989), who revisited the family. - Clinical Variability Gorlin et al. (2001) noted that there is markedly variable expressivity of Greig cephalopolysyndactyly syndrome, and that craniosynostosis has been rarely reported. Hootnick and Holmes (1972) reported a father with polysyndactyly and his son with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum (McDonald-McGinn et al., 2010). Gorlin et al. (2001) considered the father and son reported by Hootnick and Holmes (1972) had GCPS. Guzzetta et al. (1996) reported a boy with trigonocephaly and digital anomalies, including syndactyly of the third and fourth fingers of both hands with bony fusion, bifid thumbs, preaxial polydactyly of the toes, and syndactyly of the first, second, and third rays of the feet. He also had partial agenesis of the corpus callosum but normal development at age 11 months. Guzzetta et al. (1996) discussed the differential diagnosis as including GCPS and Carpenter syndrome (see 201000), and Fryns et al. (1997) later noted the phenotypic overlap with acrocallosal syndrome (ACLS; 200990). McDonald-McGinn et al. (2010) reported 2 unrelated patients with craniosynostosis of the metopic suture resulting in trigonocephaly and multiple digital anomalies associated with 2 different heterozygous mutations in the GLI3 gene (165240.0020 and 165240.0021, respectively). One patient had full digit postaxial polydactyly of all 4 limbs, whereas the other had bilateral complete cutaneous syndactyly of the third and fourth fingers, duplication of the great toe on the right with soft tissue syndactyly of toes 2 and 3, and medial deviation of the great toe on the left. Neither patient had structural brain anomalies, and both had normal development at ages 14 months and 13 years, respectively. The presence of trigonocephaly expanded the phenotype associated with GLI3 mutations. Kini et al. (2010) also reported a child with Greig syndrome and metopic synostosis resulting from a GLI3 mutation. The child also had speech delay. Biesecker (2008) reviewed GCPS, noting the phenotypic overlap with acrocallosal syndrome (ACLS; 200990). He remarked that in patients with substantial phenotypic overlap, molecular diagnostics are essential to arrive at a correct diagnosis; a mutation in GLI3 denotes GCPS. He classified the patient of Elson et al. (2002), with a phenotype 'indistinguishable from acrocallosal syndrome,' as a case of GCPS (see 165240.0013).
Using FISH and STRP analyses in the study of 34 patients with characteristics of GCPS, Johnston et al. (2003) found that 11 had deletions. Mental retardation or developmental delay was present in 9 patients with deletions in whom ... Using FISH and STRP analyses in the study of 34 patients with characteristics of GCPS, Johnston et al. (2003) found that 11 had deletions. Mental retardation or developmental delay was present in 9 patients with deletions in whom the disorder was classified as severe GCPS. These patients had manifestations that overlapped with the acrocallosal syndrome. The deletion breakpoints were analyzed in 6 patients whose deletions ranged in size from 151 kb to 10.6 Mb. Junction fragments were found to be distinct with no common sequences flanking the breakpoints. Johnston et al. (2003) concluded that patients with GCPS caused by large deletions that include GLI3 are likely to have cognitive deficits, and hypothesized that the severe GCPS phenotype is caused by deletion of contiguous genes. Johnston et al. (2005) hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause Pallister-Hall syndrome (PHS; 146510), whereas haploinsufficiency of GLI3 causes GCPS. To test this hypothesis, they screened 46 patients with PHS and 89 patients with GCPS for GLI3 mutations. They detected 47 pathologic mutations (among 60 probands), and when these mutations were combined with previously published mutations, 2 genotype-phenotype correlations were evident. GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Among the frameshift/nonsense mutations, Johnston et al. (2005) found a clear genotype/phenotype correlation. Mutations in the first third of the gene (from open reading frame nucleotides 1-1997) caused GCPS, and mutations in the second third of the gene (from nucleotides 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3-prime third of the gene (after open reading frame nucleotide 3481), and no patients with PHS had mutations in this region. These results demonstrated a robust genotype/phenotype correlation for GLI3 mutations and strongly supported the hypothesis that these 2 allelic disorders have distinct modes of pathogenesis. Furniss et al. (2007) identified a heterozygous nonsense mutation in the GLI3 gene (R792X; 165240.0016) in a patient with GCPS. The mutation was demonstrated to result in nonsense-mediated mRNA decay. Furniss et al. (2007) postulated that the relatively mild phenotype in this patient, which was less severe than that observed in Pallister-Hall syndrome, may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein.
Vortkamp et al. (1991) used a candidate gene approach to test the possible implication of the GLI3 gene in this disorder, since the GLI3 gene had been mapped to 7p13. Vortkamp et al. (1991) demonstrated that 2 of ... Vortkamp et al. (1991) used a candidate gene approach to test the possible implication of the GLI3 gene in this disorder, since the GLI3 gene had been mapped to 7p13. Vortkamp et al. (1991) demonstrated that 2 of 3 translocations found to be associated with GCPS interrupt the GLI3 gene. The breakpoints were within the first third of the coding sequence. In the third translocation, chromosome 7 was broken at about 10 kb downstream of the 3-prime end of GLI3. In patients with GCPS, Wild et al. (1997) identified heterozygous point mutations in the GLI3 gene (165240.0018 and 165240.0019). Sobetzko et al. (2000) described a newborn infant with an unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia. A history of digital anomalies in the father and grandfather led to the diagnosis of Greig cephalopolysyndactyly syndrome. The skeletal changes were thought to fit best congenital spondyloepiphyseal dysplasia (SEDC; 183900), a type II collagen disorder. Molecular analysis confirmed the presence of 2 dominant mutations in the infant: a GLI3 mutation (E543X; 165240.0010), which was present also in the father and grandfather, and a de novo COL2A1 mutation leading to a gly973 to arg (G973R; 120140.0031) substitution. Thus, this boy combined the syndactyly-macrocephaly phenotype of Greig syndrome with a severe form of SED caused by de novo mutation in type II collagen. The diagnostic difficulties posed by the combination of 2 genetic disorders and the usefulness of molecular diagnostics were well illustrated. Debeer et al. (2003) presented clinical and radiologic findings of 12 patients with GCPS derived from 4 independent families and 3 sporadic cases with documented GLI3 mutations, with particular emphasis on inter- and intrafamilial variability. In a particularly instructive family in which 9 members of 4 generations could be studied clinically and molecularly, a missense mutation, R625W (165240.0012), was transmitted and showed a partially penetrant pattern. In a branch of the family, the GCPS phenotype skipped a generation via a normal female carrier without clinical signs, providing evidence that GCPS does not always manifest full penetrance. Hurst et al. (2011) studied 5 sporadic patients with trigonocephaly due to metopic synostosis in association with pre- and postaxial polydactyly and cutaneous syndactyly of the hands and feet. In all 5 children, diagnosis of GCPS was confirmed by molecular analysis of GLI3, which revealed heterozygosity for a missense mutation and a nonsense mutation in 2 patients, respectively, as well as 3 complete gene deletions detected by array CGH in the remaining 3 patients. Three of the patients had been referred with a clinical diagnosis of Carpenter syndrome (see 201000), which shows overlapping features with GCPS, including craniosynostosis and polysyndactyly; however, additional features that would point to Carpenter syndrome, such as fusion of the coronal or lambdoid sutures, high birth weight, umbilical hernia, and hypogenitalism in males, were absent in these patients. Hurst et al. (2011) also noted that 1 of these patients had hypoplasia of the corpus callosum, a feature that could cause confusion with acrocallosal syndrome.
Major findings of Greig cephalopolysyndactyly syndrome (GCPS) are the following:...
DiagnosisClinical DiagnosisMajor findings of Greig cephalopolysyndactyly syndrome (GCPS) are the following:Macrocephaly. Occipitofrontal (head) circumference (OFC) greater than 97th centile compared to appropriate age- and sex-matched normal standards [Allanson et al 2009]. Note: An enlarged OFC must be interpreted with caution in families in which a parent (or parents) of the proband has benign familial macrocephaly (OMIM 53470). Some individuals with GCPS have a high, prominent, or bossed forehead. Ocular hypertelorism. Interpupillary distance more than 2 SD above the mean (newborns 27-41 weeks’ gestational age or interpupillary distance above the 97th centile (age 0-15 years) or a subjectively increased interpupillary distance [Hall et al 2009]. Increased inner canthal distance (i.e., telecanthus, or apparent ocular hypertelorism) may be present as well but is not as distinctive a finding as increased interpupillary distance. Increased interpupillary distance is often associated with a broad nasal bridge. Preaxial polydactyly At least one limb should manifest one of the following [Biesecker et al 2009]:Preaxial polydactyly (duplication of all or part of the first ray)A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)A markedly broad thumb (increased thumb width without increased dorso-ventral dimension) Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms. Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb. Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence). Some individuals have widening of the first digit apparent only on x-ray. This is difficult to assess when diagnosing a proband. Cutaneous syndactyly. The cutaneous syndactyly may be partial or complete; in occasional severe cases, parts of the distal phalanges may be fused. A presumptive diagnosis* is established in a proband with preaxial polydactyly, cutaneous syndactyly of toes 1-3 or fingers 3-4, ocular hypertelorism, and macrocephaly. Note: The diagnosis should be made with caution in infants with multiple other malformations, especially in the absence of a positive family history. A firm diagnosis* is established in:A first-degree relative of a proband for whom the diagnosis has been independently established. The first-degree relative of a proband may be diagnosed as affected if he/she has pre- or postaxial polydactyly with or without syndactyly or the craniofacial features. Note: Postaxial polydactyly type B should not be used as a diagnostic criterion for first-degree relatives of persons who are of west-central African descent.A proband who has features of GCPS and a mutation in GLI3. *The distinction of presumptive and firm diagnoses is based on data of Johnston et al [2005], who suggested that the clinical criteria were useful but may not be sufficiently specific to warrant a "firm" diagnosis on clinical grounds alone. A small but significant fraction of individuals with features of GCPS do not have mutations in GLI3. This, coupled with the fact that the features of GCPS may be a component of many other syndromes, warrants caution in applying these diagnostic criteria.TestingCytogenetic analysis. Giemsa-banding karyotype performed at the 500-600 band level with attention directed to 7p13 detects a translocation or interstitial deletion in fewer than 5%-10% of affected individuals (see Table 1).Note: Giemsa-banded karyotypes do not detect all deletions, even those on the order of 1 Mb [unpublished observations]. Molecular Genetic Testing Gene. GLI3 is the only gene in which mutation isknown to be associated with Greig cephalopolysyndactyly syndrome. Clinical testingSequence analysis detects mutations in approximately 70% of typically affected individuals [Johnston et al 2005]. Duplication/deletion testing FISH analysis using hybridization of the labeled BAC clone to metaphase spreads detects deletions in the estimated 5%-10% of individuals with large deletions [Johnston et al 2003]. Array comparative genomic hybridization (array CGH) of GLI3. No data have been published on use of this method to detect GLI3 deletions but it is reasonable to expect that array CGH would detect a deletion that encompasses more than one target on the array. MLPA (multiplex ligation-dependent probe amplification). The general utility of MLPA is well established; however, no data demonstrating the specificity or sensitivity of this technique for GLI3 deletions or duplications have been published. Research testing. Molecular genetic testing is complicated by the wide spectrum of mutations that are known to cause GCPS. Current methodology includes the following:Sequence analysis Loss-of-heterozygosity (LOH) analysis to detect large deletions qPCR Array CGH Table 1. Summary of Molecular Genetic Testing Used in Greig Cephalopolysyndactyly SyndromeView in own windowTest MethodMutations Detected Mutation Detection Frequency 1,2Test Availability Sequence analysisGL13 sequence alterations70%Clinical FISHDeletions and duplications 3 5%-10%MLPAArray CGH Clinical LOH analysisGL13 deletions~50%-75%Research only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Proportion of affected individuals with a mutation detected by this test method Mutation rate based on Johnston et al [2005]3. To date, every person with a deletion or duplication of GLI3 has had a different breakpoint and the sizes of the deletions have ranged from one exon to more than 10 Mb [Johnston et al 2007]. Because GLI3 is about 300 kb in size, large deletions may not necessarily alter the signal of any given GLI3 FISH, array CGH, or MLPA probe. Therefore, no single testing modality can detect all such deletions and translocations, making it difficult to quote a detection rate for any single testing modality.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing StrategyConfirmation of the diagnosis in a proband1.All individuals for whom GCPS is a diagnostic consideration should have a Giemsa-banding karyotype performed at the 500-600 band level with attention directed to 7p13 to detect a translocation or interstitial deletion. 2.If the karyotype is normal, it is reasonable to proceed with sequence analysis. 3.If no GLI3 mutation is identified, it is reasonable to proceed with either FISH testing or array CGH analysis.Prenatal diagnosis for at-risk pregnancies requires prior identification of the underlying genetic cause in the family (i.e., deletion of 7p13, balanced chromosomal rearrangement, or GLI3 mutation). Genetically Related (Allelic) DisordersOther phenotypes associated with mutations in GLI3: Pallister-Hall syndrome (PHS) comprises central or postaxial polydactyly, hypothalamic hamartoma, bifid epiglottis, imperforate anus or anal stenosis, and other anomalies. PHS displays a wide range of severity. There is confusion in the literature and it is wrongly assumed that PHS is severe and Greig cephalopolysyndactyly syndrome is mild. A minority of individuals with PHS show multiple severe anomalies such as pituitary dysplasia with panhypopituitarism and laryngeal clefts or other airway anomalies, which may be life threatening in the neonatal period. However, most individuals with PHS are mildly affected with polydactyly and asymptomatic bifid epiglottis and hypothalamic hamartoma (HH). Postaxial polydactyly type A (PAP-A) is not a syndrome but instead a limb malformation limited to the presence of a single, well-formed supernumerary postaxial digit on one or both hands and feet. There is some controversy regarding whether PAP-A is distinct from PHS or is instead a mild variant of PHS with mild, subtle, and asymptomatic bifid epiglottis, hypothalamic hamartoma, anal stenosis, and other signs. Preaxial polydactyly type IV (PPD-IV) is essentially GCPS without craniofacial manifestations. Affected individuals typically have the same pattern of syndactyly in the hands and feet as individuals with GCPS. Isolated preaxial polydactyly type IV (PPDIV) comprises preaxial polydactyly of the hands and/or feet in the absence of other malformations. The severity of the PPDIV is highly variable [Everman 2006]. Because macrocephaly occurs in the general population and is common in GCPS, the presence of macrocephaly in a person with apparently isolated PPDIV may be difficult to interpret.
Several large families have been reported as having a mild form of GCPS with excellent general health and normal longevity. ...
Natural HistorySeveral large families have been reported as having a mild form of GCPS with excellent general health and normal longevity. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (estimated at <10%) of GCPS. These complications are more likely if the child has CNS malformations (rare) or hydrocephalus (uncommon), and they may be more common in individuals with large (>300 kb) deletions that encompass GLI3 [Johnston et al 2007].
Individuals who have GCPS associated with a large (>300 kbp) deletion have a more severe phenotype than those with chromosome translocations or point mutations in GLI3 [Kroisel et al 2001, Johnston et al 2007]. Individuals with large deletions appear to have a higher incidence of intellectual disability, seizures, and CNS anomalies. This phenomenon is presumably caused by haploinsufficiency of multiple genes in the vicinity of GLI3. ...
Genotype-Phenotype CorrelationsIndividuals who have GCPS associated with a large (>300 kbp) deletion have a more severe phenotype than those with chromosome translocations or point mutations in GLI3 [Kroisel et al 2001, Johnston et al 2007]. Individuals with large deletions appear to have a higher incidence of intellectual disability, seizures, and CNS anomalies. This phenomenon is presumably caused by haploinsufficiency of multiple genes in the vicinity of GLI3. One individual with a severe GCPS phenotype that overlaps with acrocallosal syndrome (see Figure 1) was found to have a missense mutation in GLI3 [Elson et al 2002].FigureFigure 1 A. The mutational spectra of GCPS and PHS are distinct. GCPS is caused by mutations of all types, whereas PHS is only caused by truncation mutations and one splice mutation that generates a frameshift and a truncation. B. Within (more...)A genotype-phenotype correlation has been demonstrated on two levels:Class of mutation. Mutations of all classes can cause GCPS whereas the only class of mutations that causes the allelic disorder Pallister-Hall syndrome is frameshifting mutations. Haploinsufficiency for GL13 causes GCPS, whereas truncation mutations 3' of the zinc finger domain of GLI3 generally cause PHS [Kang et al 1997] (Figure 1A). Mutation position. Among all frameshift mutations in GLI3, mutations in the first third of the gene are only known to cause GCPS (Figure 1B). Frameshifting mutations in the middle third of the gene cause Pallister-Hall syndrome and uncommonly cause GCPS. Frameshift mutations in the final third of the gene cause GCPS. There is no apparent correlation of the mutation position within each of the three regions and the severity of the respective phenotypes.
Acrocallosal syndrome (ACLS) includes pre- or postaxial polydactyly, syndactyly, agenesis corpus callosum (rare in GCPS), ocular hypertelorism, macrocephaly, moderate to severe intellectual disability, intracerebral cysts, seizures, and umbilical and inguinal hernias. The disorder appears to be inherited in an autosomal recessive manner [Koenig et al 2002]. The milder end of the ACLS phenotype can overlap with the severe end of the GCPS phenotype caused by interstitial deletions of 7p13 that delete GLI3 and additional neighboring genes, as discussed in Genotype-Phenotype Correlations. Nevertheless, the frequency of consanguinity, sibling recurrences with unaffected parents; and preliminary mapping data suggest that ACLS can be a disorder distinct from severe GCPS. ...
Differential DiagnosisAcrocallosal syndrome (ACLS) includes pre- or postaxial polydactyly, syndactyly, agenesis corpus callosum (rare in GCPS), ocular hypertelorism, macrocephaly, moderate to severe intellectual disability, intracerebral cysts, seizures, and umbilical and inguinal hernias. The disorder appears to be inherited in an autosomal recessive manner [Koenig et al 2002]. The milder end of the ACLS phenotype can overlap with the severe end of the GCPS phenotype caused by interstitial deletions of 7p13 that delete GLI3 and additional neighboring genes, as discussed in Genotype-Phenotype Correlations. Nevertheless, the frequency of consanguinity, sibling recurrences with unaffected parents; and preliminary mapping data suggest that ACLS can be a disorder distinct from severe GCPS. Some subtypes of oral-facial-digital syndrome have similar limb malformations [Gorlin et al 2001]. (See, for example, Oral-Facial-Digital Syndrome Type 1.) Craniofrontonasal dysplasia has similar facial features [Gorlin et al 2001].
Most patients diagnosed with Greig cephalopolysyndactyly syndrome (GCPS) have the craniofacial and limb anomalies only. As for all patients with malformations, a good dysmorphologic exam is appropriate to exclude other anomalies. ...
ManagementEvaluations Following Initial Diagnosis Most patients diagnosed with Greig cephalopolysyndactyly syndrome (GCPS) have the craniofacial and limb anomalies only. As for all patients with malformations, a good dysmorphologic exam is appropriate to exclude other anomalies. Sophisticated imaging, especially of the CNS, is not routinely indicated unless the clinician detects findings or symptoms that specifically indicate such an evaluation. Similarly, as most patients with GCPS have normal development, screening beyond the standard Denver Developmental Screening test is not recommended. Treatment of Manifestations *The author is not aware of craniofacial reconstructive surgery being performed on individuals with GCPS as the ocular hypertelorism and macrocephaly are generally not sufficiently severe to warrant surgery. Repair of polydactyly should be undertaken on an elective basis. Preaxial polydactyly of the thumbs is considered to be a higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot because of the importance of early and proper development of the prehensile grasp. Syndactyly of the fingers is usually repaired if it is more than minimal. As is true for any malformation of the feet, surgical correction must be carefully considered. Cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications. Seizures are treated symptomatically. *As in the diagnostic criteria section, no published data support these recommendations, which are those of the author. Surveillance *Individuals with an OFC that is increasing faster than normal, signs of increased intracranial pressure, developmental delay, loss of milestones, or seizures should undergo appropriate CNS imaging studies to exclude hydrocephalus, other CNS abnormalities, or cerebral cavernous malformations (seen in some patients with GCPS and large deletions [Bilguvar et al 2007; Author, unpublished observations]). *As in the diagnostic criteria section, no published data support these recommendations, which are those of the author. Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Greig Cephalopolysyndactyly Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGLI37p14.1Zinc finger protein GLI3GLI3 @ LOVDGLI3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Greig Cephalopolysyndactyly Syndrome (View All in OMIM) View in own window 165240GLI-KRUPPEL FAMILY MEMBER 3; GLI3 175700GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; GCPSMolecular Genetic PathogenesisAlterations that cause Greig cephalopolysyndactyly syndrome (GCPS) range from gross cytogenetic alterations to nucleic acid substitutions. Normal allelic variants. GLI3 is large, with exons spanning at least 296 kb of genomic DNA on the minus strand of chromosome 7, from 41,967,073-42,243,321 bp and comprising at least 15 exons in the current human genome build (genome.ucsc.edu; March 2006 build). The current reference sequence for the cDNA is an 8,228 nt sequence: NM_000168.5.A number of putative normal allelic variants exist in GLI3 (Table 2 pdf). Most of the variants have been seen in multiple unrelated persons and are not believed to be associated with any phenotypic effects, although they have not been rigorously analyzed for subtle effects. They are included in Table 2 (pdf) if they lie within an exon or if they are in an intron within 25 bp of an exon. Readers should refer to dbSNP to confirm these data and for additional data (SNPs are from Human Genome build 126).Pathologic allelic variants. A large variety of published pathologic gene variants have been reported including cytogenetically visible translocations, interstitial deletions of 7p13, small insertions or deletions that cause frameshifts and premature truncation, nonsense mutations, mutations that alter a splice site, and missense mutations that change an amino acid [Wild et al 1997, Kalff-Suske et al 1999, Elson et al 2002, Debeer et al 2003, Johnston et al 2005]. (For more information, see Table A.) Selected pathologic variants reported in individuals with GCPS are listed in Table 3 (pdf). Multiple new mutations have been identified by Johnston et al [2005]. See Table 4.Table 4. Selected GLI3 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference Sequences c.540_547delp.Asn181Cysfs*15 (p.A181_T183delinsCfs*15)NM_000168.5 NP_000159.3c.658delC p.Arg220Valfs*3c.679+2_679+15del14del14 --c.827-3C>G -- c.868C>Tp.Arg290*c.1048dupT (c.1048_1049insT)p.Tyr350Leufs*62 c.1074delCp.His358Glnfs*7c.1497+1G>C--c.1617_1633delp.Arg539Serfs*7 (p.R539_P545delinsSfs*7)c.1789C>Tp.Gln597*c.1880_1881delATp.His627Argfs*48c.2374C>Tp.Arg792*c.4119_4123delinsAGCCTGA (c.4119_4123delins7)p.Pro1374Alafs*2 (p.P1374_S1375delinsAfs*2)c.4403dupT (c.4402_4403insT)p.Leu1469Alafs*10c.4427delAp.Asn1476Thrfs*12 (p.S1477Lfs*11)c.4564delGp.Ala1522Profs*2c.4677dupC (c.4677_4678insC)p.Gly1560Argfs*38c.1446C>Gp.Cys482Trpc.1874G>Ap.Arg625Gln c.1873C>Tp.Arg625TrpJohnston et al [2005]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The gene encodes a protein of 1,580 amino acids.Note: As the result of a cDNA sequencing error, older citations described a longer open reading frame that predicted a protein of 1,596 amino acids; the error was corrected in the GenBank entry NM_000168.3 and in subsequent versions of this sequence.GLI3 encodes a zinc finger transcription factor that is downstream of Sonic Hedgehog in SHH pathway (SHH-PTCH1-SMO-GLI1, GLI2, GLI3) [Villavicencio et al 2000]. The various GLI proteins in turn regulate genes further downstream in this pathway, including HNF3β, bone morphogenetic proteins, and other as-yet-unknown targets. The human gene is similar to the mouse paralog Gli3 and the vertebrate GLI gene family is homologous to the Drosophila melanogaster gene cubitus interruptus (ci). Abnormal gene product. The most common, if not sole, pathogenetic mechanism for GCPS is haploinsufficiency. Deletions that remove the entire gene cause a GCPS phenotype that is not known to be different from that caused by point mutations. In addition, mouse models support the hypothesis that haploinsufficiency is the mechanism. Although it is clear that haploinsufficiency of GLI3 can cause GCPS, the pathogenic mechanism of 3' frameshift or nonsense mutations and missense mutations is not clear. It is important to note that mRNA or protein instability may be caused by some of these mutations in individuals with GCPS, a finding that would be entirely compatible with the general mechanism of haploinsufficiency.