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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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Oligonucleotide array CGH results for (A) case 4038 with 3.9 Mb deletion of 9q22; (B) case 2082 with 2.5 Mb duplication of 5p15, (C) case 1056 with 3.3 Mb duplication of 3p25 and (D) case 1061 with a 1.6 Mb duplication of 1q43. Results are presented as in Figure 1.
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fig02: Oligonucleotide array CGH results for (A) case 4038 with 3.9 Mb deletion of 9q22; (B) case 2082 with 2.5 Mb duplication of 5p15, (C) case 1056 with 3.3 Mb duplication of 3p25 and (D) case 1061 with a 1.6 Mb duplication of 1q43. Results are presented as in Figure 1.

Mentions: We identified one individual with metopic synostosis and a large heterozygous deletion of chromosome 9q22 encompassing 33 genes (patient 4038; Fig. 2A). Since entering the study as an infant, this patient has had severe developmental delay. There are several reports in the literature of similar interstitial deletions of 9q [Boonen et al., 2005; Redon et al., 2006; Nowakowska et al., 2007]. Two patients with large deletions of 9q22 were both described with trigonocephaly [Redon et al., 2006]. The deletion in our patient, which is smaller than the previously reported deletions, supports the hypothesis that there is a gene influencing cranial development and narrows the critical region. Although parental DNA was unavailable for analysis, all cases reported to date are de novo.


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)

Oligonucleotide array CGH results for (A) case 4038 with 3.9 Mb deletion of 9q22; (B) case 2082 with 2.5 Mb duplication of 5p15, (C) case 1056 with 3.3 Mb duplication of 3p25 and (D) case 1061 with a 1.6 Mb duplication of 1q43. Results are presented as in Figure 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Oligonucleotide array CGH results for (A) case 4038 with 3.9 Mb deletion of 9q22; (B) case 2082 with 2.5 Mb duplication of 5p15, (C) case 1056 with 3.3 Mb duplication of 3p25 and (D) case 1061 with a 1.6 Mb duplication of 1q43. Results are presented as in Figure 1.
Mentions: We identified one individual with metopic synostosis and a large heterozygous deletion of chromosome 9q22 encompassing 33 genes (patient 4038; Fig. 2A). Since entering the study as an infant, this patient has had severe developmental delay. There are several reports in the literature of similar interstitial deletions of 9q [Boonen et al., 2005; Redon et al., 2006; Nowakowska et al., 2007]. Two patients with large deletions of 9q22 were both described with trigonocephaly [Redon et al., 2006]. The deletion in our patient, which is smaller than the previously reported deletions, supports the hypothesis that there is a gene influencing cranial development and narrows the critical region. Although parental DNA was unavailable for analysis, all cases reported to date are de novo.

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