Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome

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We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment.

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Figure 1: Facial features of all subjects.

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We thank the subjects and their parents for participation in this study. We would like to acknowledge A. Hoischen for his useful suggestions regarding the interpretation of exome sequencing data. We received funding from the European Union Seventh Framework Programme for Research (FP7; 223026 (Development of Targeted DNA-Chips for High Throughput Diagnosis of NeuroMuscular Disorders (NMD-Chip)) and 223143; Technological Innovation of High Throughput Molecular Diagnostics of Clinically and Molecularly Heterogeneous Genetic Disorders (TECHGENE)). All participants in this study provided informed consent. The Leiden University Medical Center ethics committee has approved the protocol describing genetic studies in individuals with intellectual disability of unknown etiology.

Author information

G.W.E.S. analyzed the data and wrote the manuscript. E.A., G.-J.B.v.O., M.H.B., J.T.d.D., A.v.H. and M.K. conceived and designed the experiments. E.A., Y.S. and R.A. performed the experiments. C.G. contributed analysis tools. M.N., S.G.K., I.N.S., E.A.J.P., M.W.W., N.S.d.H., Y.H.-H. and A.v.H. clinically characterized the subjects. C.A.L.R. analyzed SNP array data. A.v.H. selected the subjects for sequencing. A.v.H. and M.K. jointly supervised the research. All authors contributed to the final manuscript.

Correspondence to Gijs W E Santen.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–3 (PDF 954 kb)

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Santen, G., Aten, E., Sun, Y. et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 44, 379–380 (2012) doi:10.1038/ng.2217

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