Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis.
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.
Affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. firstname.lastname@example.orgShow MeSH
Related in: MedlinePlus
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.
Affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. email@example.com