Copy number variation analysis in single‐suture craniosynostosis: Multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis

Heather C Mefford,Sarah S Park,Matthew D Smyth,Evan E Eichler,Neil Shafer,Matthew L Speltz,Francesca Antonacci,Anne V Hing,Mark J Rieder,Michael L Cunningham,Jesse M Tsai

doi:10.1002/ajmg.a.33557

Abstract

Little is known about genes that underlie isolated single-suture craniosynostosis. In this study, we hypothesize that rare copy number variants (CNV) in patients with isolated single-suture craniosynostosis contain genes important for cranial development. Using whole genome array comparative genomic hybridization (CGH), we evaluated DNA from 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications. 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. The genes within and disrupted by CNVs in this cohort are potential novel candidate genes for craniosynostosis. © 2010 Wiley-Liss, Inc.

Highlights

Craniosynostosis is defined as the premature fusion of one or more cranial sutures and has an overall prevalence of 3–5 per 10,000 individuals [French et al, 1990; Cohen, 2000; Boulet et al, 2008].Ó 2010 Wiley-Liss, Inc.AMERICAN JOURNAL OF MEDICAL GENETICS PART A in which mutations cause syndromic forms of craniosynostosis
We evaluated DNA from 186 individuals with single-suture craniosynostosis using a whole-genome oligonucleotide array comparative genomic hybridization (CGH) platform
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; the duplication was not found in the mother, as expected

Summary

INTRODUCTION

Craniosynostosis is defined as the premature fusion of one or more cranial sutures and has an overall prevalence of 3–5 per 10,000 individuals [French et al, 1990; Cohen, 2000; Boulet et al, 2008]. AMERICAN JOURNAL OF MEDICAL GENETICS PART A in which mutations cause syndromic forms of craniosynostosis. These include: FGFR1, FGFR2, FGFR3, TWIST1, MSX2, EFNB1, TGFBR1, TGFBR2, FBN1, RECQL4, RAB23, and POR [PassosBueno et al, 2008]. There are limited reports of mutations in FGFR1, FGFR2, FGFR3, and TWIST1 [Renier et al, 2000; Mulliken et al, 2004; Seto et al, 2007] in some patients with non-syndromic single-suture craniosynostosis, but these explain only a small fraction of affected individuals. With the increasing availability and use of array comparative genomic hybridization (CGH) and SNP microarrays, there are many examples of phenotypes that have been studied to evaluate for CNVs. In this study, we hypothesize that rare CNVs in patients with isolated single-suture craniosynostosis contain genes important for the phenotype. We identified several additional rare CNVs that may harbor candidate genes for craniosynostosis

METHODS

RESULTS

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DISCUSSION