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

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 03/2012; 44(4):379-80. DOI: 10.1038/ng.2217
Source: PubMed

ABSTRACT 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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    • "One highly successful strategy uses the healthy parents of a patient with a severe disease to identify genetic variants in the patient that were not inherited, termed de novo variants. In fact, disruptive de novo variants appear to cause a substantial proportion of intellectual disability and many rare genetic disorders (Hoischen et al., 2010, 2011; Vissers et al., 2010; Bartnik et al., 2011; Filges et al., 2011; Gilman et al., 2011; Girard et al., 2011; Gonzalez-del Pozo et al., 2011; Paulussen et al., 2011; Xu et al., 2011; Bujakowska et al., 2012; Dauber et al., 2012; Harakalova et al., 2012; Iossifov et al., 2012; Lederer et al., 2012; Lin et al., 2012; Neale et al., 2012; Need et al., 2012; Neveling et al., 2012; O’Roak et al., 2012b; Riviere et al., 2012; Sanders et al., 2012; Santen et al., 2012; Schrier et al., 2012; Tsurusaki et al., 2012; Van Houdt et al., 2012; Whalen et al., 2012). "
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    ABSTRACT: Next Generation Sequencing studies generate a large quantity of genetic data in a relatively cost and time efficient manner and provide an unprecedented opportunity to identify candidate causative variants that lead to disease phenotypes. A challenge to these studies is the generation of sequencing artifacts by current technologies. To identify and characterize the properties that distinguish false positive variants from true variants, we sequenced a child and both parents (trio) using DNA isolated from three sources (blood, buccal cells, and saliva). The trio strategy allowed us to identify variants in the proband that could not have been inherited from the parents (Mendelian errors) and would most likely indicate sequencing artifacts. Quality control measurements were examined and three measurements were found to identify the greatest number of Mendelian errors. These included read depth, genotype quality score, and alternate allele ratio. Filtering the variants on these measurements removed ~95% of the Mendelian errors while retaining 80% of the called variants. These filters were applied independently. After filtering, the concordance between identical samples isolated from different sources was 99.99% as compared to 87% before filtering. This high concordance suggests that different sources of DNA can be used in trio studies without affecting the ability to identify causative polymorphisms. To facilitate analysis of next generation sequencing data, we developed the Cincinnati Analytical Suite for Sequencing Informatics (CASSI) to store sequencing files, metadata (e.g. relatedness information), file versioning, data filtering, variant annotation, and identify candidate causative polymorphisms that follow either de novo, rare recessive homozygous or compound heterozygous inheritance models. We conclude the data cleaning process improves the signal to noise ratio in terms of variants and facilitates the identification of candidate disease causative polymorphisms.
    Frontiers in Genetics 02/2014; 5:16. DOI:10.3389/fgene.2014.00016
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    • "These complexes are involved in maintaining normal cellular functions and restricting the access of regulatory factors to nucleosomal DNA [16]. The ARID1B gene has been suggested to be associated with the occurrence of Coffin-Siris syndrome [17], a multiple congenital anomaly/mental retardation syndrome characterized by mild to moderate mental retardation, moderate to severe hypotonia, epilepsy, and congenital malformation, including a coarse facial appearance and incompletely formed fifth fingers and toes. Haploinsufficiency of the ARID1B gene is speculated to be a common potential cause of intellectual disability and speech impairment. "
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    ABSTRACT: Bilateral sagittal split ramus osteotomy (BSSRO) is a common orthognatic surgical procedure. Sensory disturbances in the inferior alveolar nerve, including hypoesthesia and dysesthesia, are frequently observed after BSSRO, even without distinct nerve injury. The mechanisms that underlie individual differences in the vulnerability to sensory disturbances have not yet been elucidated. The present study investigated the relationships between genetic polymorphisms and the vulnerability to sensory disturbances after BSSRO in a genome-wide association study (GWAS). A total of 304 and 303 patients who underwent BSSRO were included in the analyses of hypoesthesia and dysesthesia, respectively. Hypoesthesia was evaluated using the tactile test 1 week after surgery. Dysesthesia was evaluated by interview 4 weeks after surgery. Whole-genome genotyping was conducted using Illumina BeadChips including approximately 300,000 polymorphism markers. Hypoesthesia and dysesthesia occurred in 51 (16.8%) and 149 (49.2%) subjects, respectively. Significant associations were not observed between the clinical data (i.e., age, sex, body weight, body height, loss of blood volume, migration length of bone fragments, nerve exposure, duration of anesthesia, and duration of surgery) and the frequencies of hypoesthesia and dysesthesia. Significant associations were found between hypoesthesia and the rs502281 polymorphism (recessive model: combined chi2 = 24.72, nominal P = 6.633 x 10-7), between hypoesthesia and the rs2063640 polymorphism (recessive model: combined chi2 = 23.07, nominal P = 1.563 x 10-6), and between dysesthesia and the nonsynonymous rs2677879 polymorphism (trend model: combined chi2 = 16.56, nominal P = 4.722 x 10-5; dominant model: combined chi2 = 16.31, nominal P = 5.369 x 10-5). The rs502281 and rs2063640 polymorphisms were located in the flanking region of the ARID1B and ZPLD1 genes on chromosomes 6 and 3, whose official names are "AT rich interactive domain 1B (SWI1-like)" and "zona pellucida-like domain containing 1," respectively. The rs2677879 polymorphism is located in the METTL4 gene on chromosome 18, whose official name is "methyltransferase like 4." The GWAS of sensory disturbances after BSSRO revealed associations between genetic polymorphisms located in the flanking region of the ARID1B and ZPLD1 genes and hypoesthesia and between a nonsynonymous genetic polymorphism in the METTL4 gene and dysesthesia.
    Molecular Pain 07/2013; 9(1):34. DOI:10.1186/1744-8069-9-34 · 3.65 Impact Factor
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    • "There were no deleterious mutations such as stops or frameshift mutations in any of the chromatin remodeling genes SMARCA2, SMARCA4, SMARCE1, SMARCB1, ARID1A and ARID1B, recently reported to be mutated in CSS [3], [4]. However, synonymous and non-synonymous single nucleotide variations were found in SMARCA2, SMARCA4, SMARCB1 and ARID1B and in other members of the SMARCA and ARID gene families, SMARCA5, SMARCAD1, ARID3A, ARID3C and ARID4A (Table 1). "
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    ABSTRACT: We characterized the t(7;22)(q32;q11.2) chromosomal translocation in an obese female with coarse features, short stature, developmental delay and a hypoplastic fifth digit. While these clinical features suggest Coffin-Siris Syndrome (CSS), we excluded a CSS diagnosis by exome sequencing based on the absence of deleterious mutations in six chromatin-remodeling genes recently shown to cause CSS. Thus, molecular characterization of her translocation could delineate genes that underlie other syndromes resembling CSS. Comparative genomic hybridization microarrays revealed on chromosome 7 the duplication of a 434,682 bp region that included the tail end of an uncharacterized gene termed C7orf58 (also called CPED1) and spanned the entire WNT16 and FAM3C genes. Because the translocation breakpoint on chromosome 22 did not disrupt any apparent gene, her disorder was deemed to result from the rearrangement on chromosome 7. Mapping of yeast and bacterial artificial chromosome clones by fluorescent in situ hybridization on chromosome spreads from this patient showed that the duplicated region and all three genes within it were located on both derivative chromosomes 7 and 22. Furthermore, DNA sequencing of exons and splice junctional regions from C7orf58, WNT16 and FAM3C revealed the presence of potential splice site and promoter mutations, thereby augmenting the detrimental effect of the duplicated genes. Hence, dysregulation and/or disruptions of C7orf58, WNT16 and FAM3C underlie the phenotype of this patient, serve as candidate genes for other individuals with similar clinical features and could provide insights into the physiological role of the novel gene C7orf58.
    PLoS ONE 12/2012; 7(12):e52353. DOI:10.1371/journal.pone.0052353 · 3.23 Impact Factor
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