Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome

Johnston, Jennifer J.; Olivos-Glander, Isabelle; Turner, Joyce; Aleck, Kyrieckos; Bird, Lynne M.; Mehta, Lakshmi; Schimke, R. Neil; Heilstedt, Heidi A.; Spence, J. Edward; Blancato, Jan; Biesecker, Leslie G.

doi:10.1002/ajmg.a.20318

Cited by 51 publications

(59 citation statements)

References 15 publications

(13 reference statements)

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“…ACS shows significant overlap with GCPS, and it has been noted that clinical diagnostic criteria are not always sufficient to distinguish between both disorders. 22 GCPS, caused by mutations in GLI3, 23,24 comprises predominantly postaxial polydactyly of the hands and preaxial polydactyly of the feet, syndactyly and craniofacial abnormalities such as broad nasal root, macrocephaly, hydrocephalus and ear abnormalities. 25 With respect to the neurological involvement, the GCPS phenotype is thought to be milder than the phenotype observed in ACS, although corpus callosum abnormalities and mental retardation have been described in some patients.…”

Section: Ihh Duplication In Acsmentioning

confidence: 99%

“…25 With respect to the neurological involvement, the GCPS phenotype is thought to be milder than the phenotype observed in ACS, although corpus callosum abnormalities and mental retardation have been described in some patients. 22 In order to exclude a severe presentation of GCPS in our cases, we initially excluded mutations in GLI3 in the index patient. We conclude that the phenotype of the siblings described here belongs to the same clinical spectrum as ACS and GCPS.…”

Section: Ihh Duplication In Acsmentioning

confidence: 99%

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A large duplication involving the IHH locus mimics acrocallosal syndrome

et al. 2012

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Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a B600-kb deletion 5¢ of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a B900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35.

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Section: Ihh Duplication In Acsmentioning

confidence: 99%

Section: Ihh Duplication In Acsmentioning

confidence: 99%

A large duplication involving the IHH locus mimics acrocallosal syndrome

et al. 2012

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“…Finally, the extent of the aneusomy is correlated with prognosis. 4 Although GCPS has a low overall rate of mental retardation and other central nervous system abnormalities, nearly all of the patients at risk for these complications are those with large deletions (.2 Mb). Therefore, this is a technically challenging problem, with high clinical relevance and utility.…”

Section: Discussionmentioning

confidence: 99%

Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes

Johnston

Walker

Davis

et al. 2006

Journal of Medical Genetics

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Contiguous gene syndromes cause disorders via haploinsufficiency for adjacent genes. Some contiguous gene syndromes (CGS) have stereotypical breakpoints, but others have variable breakpoints. In CGS that have variable breakpoints, the extent of the deletions may be correlated with severity. The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS-CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. In addition, non-CGS GCPS can be caused by deletions or duplications in GLI3. Although fluorescence in situ hybridisation (FISH) can identify large deletion mutations in patients with GCPS or GCPS-CGS, it is not practical for identification of small intragenic deletions or insertions, and it is difficult to accurately characterise the extent of the large deletions using this technique. We have designed a custom comparative genomic hybridisation (CGH) array that allows identification of deletions and duplications at kilobase resolution in the vicinity of GLI3. The array averages one probe every 730 bp for a total of about 14 000 probes over 10 Mb. We have analysed 16 individuals with known or suspected deletions or duplications. In 15 of 16 individuals (14 deletions and 1 duplication), the array confirmed the prior results. In the remaining patient, the normal CGH array result was correct, and the prior assessment was a false positive quantitative polymerase chain reaction result. We conclude that high-density CGH array analysis is more sensitive than FISH analysis for detecting deletions and provides clinically useful results on the extent of the deletion. We suggest that high-density CGH array analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions. G enetic disorders can be caused by an enormously broad range of genomic aberrations. These range from singlenucleotide point mutations to duplications and deletions of millions of basepairs of DNA, up to entire chromosomes, as in Down's syndrome. An ongoing challenge for genetic diagnostics is to develop methods to sensitively and specifically diagnose this entire range of mutations. Although current methods reliably detect the largest and smallest mutations (microscopic cytogenetics and sequencing, respectively), the middle range of mutations is difficult to detect. We dealt with this challenge by applying the evolving technology of arraybased comparative genomic hybridisation (CGH) to a disorder that is caused by a wide range of mutations, including mutations in this intermediate range.Haploinsufficiency of the transcription factor gene GLI3, on chromosome 7p14.1, causes Greig cephalopolysyndactyly syndrome (GCPS).1 Many mutations have been identified, including translocations and large genomic deletions, as well as small intragenic deletions or duplications 2 and point mutations.2 3 This wide range of mutations complicates molecular diagnostics, requiring numerous tests to detect all possible mutations. In addition, when...

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“…Mutations shown to cause GCPS include nonsense, missense, and splicing mutations, and translocations, deletions and insertions [6][7][8][9][10][11][12][13][14][15]. The deletions range from a single nucleotide to nearly a megabase in size.…”

Section: Etiologymentioning

confidence: 99%

Greig Cephalopolysyndactyly Syndrome

2012

Atlas of Genetic Diagnosis and Counseling

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The Greig cephalopolysyndactyly syndrome (GCPS) is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of incidence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000). The primary findings include hypertelorism, macrocephaly with frontal bossing, and polysyndactyly. The polydactyly is most commonly preaxial of the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment.

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Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome

Cited by 51 publications

References 15 publications

A large duplication involving the IHH locus mimics acrocallosal syndrome

A large duplication involving the IHH locus mimics acrocallosal syndrome

Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes

Greig Cephalopolysyndactyly Syndrome

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