Abstract
Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin–Siris (CSS) and Nicolaides–Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.
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Acknowledgements
We are grateful to the families for participating in this study. We thank Sabine Kaya and Daniela Falkenstein for excellent technical assistance. This work was supported in part by the German Ministry of Research and Education [Grant Numbers 01GS08164 (HE), 01GS08167 (DW), 01GS08163 (TMS), German Mental Retardation Network] as part of the National Genome Research Network and 01GM1520E (DW) as part of the Chromatin-Net consortium. Exome sequencing on Individual 2 was supported by a Grant from Dart NeuroScience LLC (FVB and OC).
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Supplemental Fig. 1: X-ray image of the left hand of individual 2 displaying hypoplastic distal phalanges (TIFF 25738 kb)
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Bramswig, N.C., Caluseriu, O., Lüdecke, HJ. et al. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin–Siris syndrome-like phenotype. Hum Genet 136, 297–305 (2017). https://doi.org/10.1007/s00439-017-1757-z
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DOI: https://doi.org/10.1007/s00439-017-1757-z