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Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis.

Mefford HC, Shafer N, Antonacci F, Tsai JM, Park SS, Hing AV, Rieder MJ, Smyth MD, Speltz ML, Eichler EE, Cunningham ML - Am. J. Med. Genet. A (2010)

Bottom Line: We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia.Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance.In addition, we find that a total of 7.5% of individuals with single-suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. hmefford@uw.edu

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Duplication of chromosome 6p21 encompassing RUNX2 in two affected cousins. A: Oligonucleotide array CGH results for cases 1007 and 1019 for chr6:44,700,000–46,500,000 (NCBI Build 36). For each individual, deviations of probe log2 ratios from zero are depicted by gray/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively. Yellow shading represents extent of duplication based on follow-up high-density array CGH validation. Red bars show the mapped location of fosmids used for FISH. B: Pedigree showing relationship of cases 1007 and 1019 and phenotypic features. The father of 1019 is a presumed carrier of the duplication but DNA was not available for analysis. C: FISH analysis using two fosmid probes shows that the duplication is tandem (see metaphase spread, upper left) and inverted (see interphase nucleus, lower right). Results are shown for patient 1019; similar results were obtained for patient 1007. White arrows indicate chromosome 6 homolog carrying the inverted duplication. The normal chromosome 6 in the metaphase spread is indicated by the “>.”
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fig01: Duplication of chromosome 6p21 encompassing RUNX2 in two affected cousins. A: Oligonucleotide array CGH results for cases 1007 and 1019 for chr6:44,700,000–46,500,000 (NCBI Build 36). For each individual, deviations of probe log2 ratios from zero are depicted by gray/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively. Yellow shading represents extent of duplication based on follow-up high-density array CGH validation. Red bars show the mapped location of fosmids used for FISH. B: Pedigree showing relationship of cases 1007 and 1019 and phenotypic features. The father of 1019 is a presumed carrier of the duplication but DNA was not available for analysis. C: FISH analysis using two fosmid probes shows that the duplication is tandem (see metaphase spread, upper left) and inverted (see interphase nucleus, lower right). Results are shown for patient 1019; similar results were obtained for patient 1007. White arrows indicate chromosome 6 homolog carrying the inverted duplication. The normal chromosome 6 in the metaphase spread is indicated by the “>.”

Mentions: We evaluated DNA from 186 individuals with single-suture craniosynostosis using a whole-genome oligonucleotide array CGH platform. We identified 14 individuals (7.5%) with at least one CNV that contained one or more genes and that has not been previously identified in 2,493 control individuals [Itsara et al., 2009] (Table I). The rare CNVs identified range from 35 kb to 3.9 Mb. Three patients (1.6%) harbored events >2 Mb compared to 8/2,493 controls (0.3%). DNA from one or more parents was available for analysis in seven cases. For four individuals, we confirmed that the CNV was inherited from a reportedly normal parent. In one case (4038), the deletion is absent in the mother, but DNA from the father was unavailable. For patient 1019 harboring a duplication of the RUNX2 gene, inheritance is presumed to be paternal given the presence of the same duplication in a first cousin and paternal aunt (see below; Fig. 1); the duplication was not found in the mother, as expected. Parents were unavailable in the remaining seven cases. Case descriptions for individuals harboring events >1 Mb are below.


Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis.

Mefford HC, Shafer N, Antonacci F, Tsai JM, Park SS, Hing AV, Rieder MJ, Smyth MD, Speltz ML, Eichler EE, Cunningham ML - Am. J. Med. Genet. A (2010)

Duplication of chromosome 6p21 encompassing RUNX2 in two affected cousins. A: Oligonucleotide array CGH results for cases 1007 and 1019 for chr6:44,700,000–46,500,000 (NCBI Build 36). For each individual, deviations of probe log2 ratios from zero are depicted by gray/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively. Yellow shading represents extent of duplication based on follow-up high-density array CGH validation. Red bars show the mapped location of fosmids used for FISH. B: Pedigree showing relationship of cases 1007 and 1019 and phenotypic features. The father of 1019 is a presumed carrier of the duplication but DNA was not available for analysis. C: FISH analysis using two fosmid probes shows that the duplication is tandem (see metaphase spread, upper left) and inverted (see interphase nucleus, lower right). Results are shown for patient 1019; similar results were obtained for patient 1007. White arrows indicate chromosome 6 homolog carrying the inverted duplication. The normal chromosome 6 in the metaphase spread is indicated by the “>.”
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104131&req=5

fig01: Duplication of chromosome 6p21 encompassing RUNX2 in two affected cousins. A: Oligonucleotide array CGH results for cases 1007 and 1019 for chr6:44,700,000–46,500,000 (NCBI Build 36). For each individual, deviations of probe log2 ratios from zero are depicted by gray/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively. Yellow shading represents extent of duplication based on follow-up high-density array CGH validation. Red bars show the mapped location of fosmids used for FISH. B: Pedigree showing relationship of cases 1007 and 1019 and phenotypic features. The father of 1019 is a presumed carrier of the duplication but DNA was not available for analysis. C: FISH analysis using two fosmid probes shows that the duplication is tandem (see metaphase spread, upper left) and inverted (see interphase nucleus, lower right). Results are shown for patient 1019; similar results were obtained for patient 1007. White arrows indicate chromosome 6 homolog carrying the inverted duplication. The normal chromosome 6 in the metaphase spread is indicated by the “>.”
Mentions: We evaluated DNA from 186 individuals with single-suture craniosynostosis using a whole-genome oligonucleotide array CGH platform. We identified 14 individuals (7.5%) with at least one CNV that contained one or more genes and that has not been previously identified in 2,493 control individuals [Itsara et al., 2009] (Table I). The rare CNVs identified range from 35 kb to 3.9 Mb. Three patients (1.6%) harbored events >2 Mb compared to 8/2,493 controls (0.3%). DNA from one or more parents was available for analysis in seven cases. For four individuals, we confirmed that the CNV was inherited from a reportedly normal parent. In one case (4038), the deletion is absent in the mother, but DNA from the father was unavailable. For patient 1019 harboring a duplication of the RUNX2 gene, inheritance is presumed to be paternal given the presence of the same duplication in a first cousin and paternal aunt (see below; Fig. 1); the duplication was not found in the mother, as expected. Parents were unavailable in the remaining seven cases. Case descriptions for individuals harboring events >1 Mb are below.

Bottom Line: We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia.Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance.In addition, we find that a total of 7.5% of individuals with single-suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. hmefford@uw.edu

Show MeSH
Related in: MedlinePlus