Nature GeNetics VOLUME 44 | NUMBER 4 | APRIL 2012
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.
Coffin-Siris syndrome (MIM 135900)1 is characterized by devel-
opmental delay, severe speech impairment, coarse facial features,
hypertrichosis, hypoplastic or absent fifth fingernails or toenails2
and agenesis of the corpus callosum (Supplementary Table 1). Few
affected individuals in published reports fulfill the complete spectrum
of the CSS phenotype, and it is a subject of debate whether all indi-
viduals with CSS have the same syndrome. CSS is generally assumed
to be inherited in an autosomal recessive manner, although autosomal
dominant inheritance has not been formally excluded3,4.
To identify the genetic cause of CSS, we performed whole-exome
sequencing in affected individuals (cases), including in one case-parent
trio and in two sporadic cases with a clinical CSS diagnosis, all of whom
were diagnosed in one hospital by the same clinical geneticist (Fig. 1,
Supplementary Fig. 1, Supplementary Tables 1 and 2 and Supplementary
Methods; exome sequencing data are available upon request).
ARID1B variants have been submitted to the Leiden Open Variation
Database (see URLs). Using the sequence analysis pipeline from the
Genome Analysis Toolkit (GATK)5,6, we identified 12,722–14,642
exonic and/or splice-site variants per individual. Filtering steps using
variant databases (dbSNP132 and the 1000 Genomes Project data-
base) and selection for coding regions revealed variants in 34 genes
that were shared by all three affected individuals. After filtering for
recessive inheritance (discarding all genes with only one hetero-
zygous variant), no gene was found to be in agreement with a recessive
inheritance model in all three cases. Accepting a dominant inheritance
mechanism, we queried heterozygous and de novo variants and identified
ARID1B as the only affected gene in all cases (Supplementary Table 3).
All variants truncated the ARID1B reading frame (two nonsense vari-
ants: c.5329A>T (p.Lys1777*) and c.3223C>T (p.Arg1075*) and one
frameshift: c.4619_4628del (p.Gln1541Argfs*35)) (Table 1). The
mutations were validated using Sanger sequencing and shown to occur
de novo in all three individuals (Supplementary Fig. 2). With it not
previously being possible to rule out an autosomal recessive inheritance
mechanism, the parents of an individual affected with CSS received a
recurrence risk of 10% (ref. 7). The identification of de novo mutations
in ARID1B in CSS cases allowed us to reduce this risk to 1–2% (ref. 8).
We queried our in-house database of individuals screened for intel-
lectual disability for potential CNVs including ARID1B. The screened
cohort consisted of individuals with intellectual disability and/or congen-
ital malformations (syndromic and non-syndromic) who were referred
for array-based CNV analysis. In this analysis, we identified 3 subjects
out of 2,000 with a deletion affecting ARID1B (Fig. 1, Supplementary
Figs. 1 and 3 and Supplementary Table 1). In comparison, six subjects
were found to have the relatively frequent 22q11.2 duplication in this
cohort. Subject 4 had a de novo 2.72-Mb deletion of the 6q25 band
Mutations in SWI/SNF chromatin
remodeling complex gene ARID1B
cause Coffin-Siris syndrome
Gijs W E Santen1, Emmelien Aten1, Yu Sun1, Rowida Almomani1,
Christian Gilissen2, Maartje Nielsen1, Sarina G Kant1, Irina N Snoeck3,
Els A J Peeters3, Yvonne Hilhorst-Hofstee1, Marja W Wessels4,
Nicolette S den Hollander1, Claudia A L Ruivenkamp1,
Gert-Jan B van Ommen1, Martijn H Breuning1, Johan T den Dunnen1,5,
Arie van Haeringen1,6,7 & Marjolein Kriek1,7
1Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 2Department of Human Genetics, Nijmegen Centre for Molecular
Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3Department of Child
Neurology, Juliana Children’s Hospital–Haga Teaching Hospital, The Hague, The Netherlands. 4Department of Clinical Genetics, Erasmus Medical Center, Rotterdam,
The Netherlands. 5Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands. 6Department of Clinical Genetics, Juliana Children’s
Hospital–Haga Teaching Hospital, The Hague, The Netherlands. 7These authors jointly directed this work. Correspondence should be addressed to G.W.E.S. (email@example.com).
Received 16 December 2011; accepted 8 February 2012; published online 18 March 2012; doi:10.1038/ng.2217
Figure 1 Facial features of all subjects. Top, left to right: subject 1 at 4.5
years, subject 2 at 2.5 years and subject 3 at 3 years. Bottom, left to right:
subject 4 at 3.5 years, subject 5 at 45 years and subject 6 at 3.5 years. All
subjects share coarse facial features, thick eyebrows and broad nasal tips. For
further details, see Supplementary Table 1. The parents or legal guardians of
all affected individuals gave consent for publication of the clinical photographs.
© 2012 Nature America, Inc. All rights reserved.
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VOLUME 44 | NUMBER 4 | APRIL 2012 Nature GeNetics
encompassing the ARID1B, C6orf35, ZDHHC14, SNX9 and SYNJ2 loci.
Subject 5 had a de novo 0.73-Mb deletion spanning the ARID1B, C6orf35
and ZDHHC14 loci, while subject 6 had a de novo deletion of 0.88 Mb
encompassing the same genes as in subject 5. Analysis of the pheno-
types of these individuals showed that, similar to our subjects with CSS,
they had moderate-to-severe intellectual disability and severe speech
delay. These individuals also had facial similarities with the subjects
with CSS (Fig. 1) but lacked some typical CSS abnormalities, such as
hypoplastic or absent fingernails or toenails. A possible diagnosis of
these individuals with CSS was considered only for subject 4 because
of her hypoplastic fingernails (Supplementary Table 1). A previous
study described eight individuals with intellectual disability and speech
impairment with haploinsufficiency of ARID1B (in one subject the gene
was disrupted by a reciprocal translocation)9. Disruption of ARID1B, as
well as de novo intragenic deletion, has also been reported in individuals
with either corpus callosum agenesis or autism9,10. Although the sizes of
the published deletions range from <1 Mb to >14 Mb, the phenotypes of
the affected individuals largely overlap with those of our CSS cases, with
the exception of the fifth finger abnormalities typical to CSS. Disruption
of ARID1B therefore seems to be the main driver of the observed CSS
phenotype, and a diagnosis of CSS should be considered in all individu-
als with intellectual disability and speech impairment, particularly when
these clinical features occur in combination with agenesis of the corpus
callosum. On the basis of these findings, we conclude that haploinsuf-
ficiency of ARID1B is likely to be an important cause of CSS.
The publicly available Database of Chromosomal Imbalance and
Phenotype in Humans Using Ensembl Resources (DECIPHER) con-
tains 12 individuals with haploinsufficiency of ARID1B (including the 3
described here and the 8 that were described previously9). As all deletions
and mutations published thus far have been de novo, disease penetrance
is expected to be high. No truncating or splice-site mutations are present
in the 1000 Genomes Project database or in the ~5,400 exomes of the
Exome Variant Server. However, the Database of Genomic Variants
includes two deletions that encompass exon 1 and exons 2–20 of the
ARID1B gene, respectively. This could signify reduced penetrance, but an
alternative explanation could be that these deletions represent a technical
artifact. Both deletions were not validated using alternative methods.
Along with ARID1A, ARID1B encodes an AT-rich interactive domain
(ARID) protein, a subunit of the Brahma-associated factor (BAF) complex.
BAF is one of the two main components of the SWItch/sucrose nonfer-
mentable (SWI/SNF)-like chromatin remodeling complex, which acts as
an epigenetic modifier by altering chromatin structure, thereby facilitating
the access of transcription factors to DNA. ARID1A and ARID1B proteins
have antagonistic functions and are both important for cell cycle regulation.
Although ARID1B is predominantly expressed in differentiated cell types, it
has also been suggested to be involved in early development of the brain11.
ARID1A is more abundantly expressed in
embryonic tissue, and somatic mutations in
this gene have recently been associated with
gastric cancer12. It was also noted recently that
histone modifying proteins seem to have a dual
role, functioning both in developmental disor-
ders and malignancies13. One could hypothesize
that activating mutations in ARID1A might give
a clinical phenotype similar to CSS.
In conclusion, CSS can be added to a grow-
ing list of syndromes characterized by congen-
ital malformations and intellectual disability
that are caused by mutations in genes that
encode modifiers of chromatin structure14,15.
URLs. DECIPHER, http://decipher.sanger.ac.uk/; Exome Variant
Server, http://evs.gs.washington.edu/EVS/; ARID1B gene variant
Accession code. The human ARID1B sequence is available from
GenBank under accession NM_020732.3.
Note: Supplementary information is available on the Nature Genetics website.
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.
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.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
Published online at http://www.nature.com/naturegenetics/.
Reprints and permissions information is available online at http://www.nature.com/
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Table 1 overview of the detected variants and cnVs affecting ARID1B
(DECIPHER ID) Chr.Position
4 (248472)62.72 Mb––––
5 (250455)6 0.73 Mb––––
6 (257917)60.88 Mb––––
Variants are mapped to the hg19 reference genome. Deletion size represents the maximum deletion. All variants
occurred de novo. Chr., chromosome. Subjects 4 and 5 were published previously9.
© 2012 Nature America, Inc. All rights reserved.