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. 2012 Mar 9;90(3):565-72.
doi: 10.1016/j.ajhg.2012.02.007.

Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability

Juliane Hoyer  1 , Arif B Ekici, Sabine Endele, Bernt Popp, Christiane Zweier, Antje Wiesener, Eva Wohlleber, Andreas Dufke, Eva Rossier, Corinna Petsch, Markus Zweier, Ina Göhring, Alexander M Zink, Gudrun Rappold, Evelin Schröck, Dagmar Wieczorek, Olaf Riess, Hartmut Engels, Anita Rauch, André Reis
Affiliations

Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability

Juliane Hoyer et al. Am J Hum Genet. .

Abstract

Intellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders.

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Figures

Figure 1
Figure 1
Summary of the Nine De Novo CNVs and Point Mutations Detected in ARID1B (A) De novo deletion in patient 1 detected with molecular karyotyping by the Affymetrix SNP6.0 platform. The signal reduction of 1,568 markers indicating the deletion region is detected only in patient 1 (red dots) and is absent in both parents. (B) 2.5 Mb deletion (red bar) in chromosomal region 6q25, which includes five RefSeq genes, among them ARID1B. Two gray scales are illustrating two different chromosomal bands as indicated in the horizontal bars. Genomic positions are in million bp. (C) Genomic structure of ARID1B. Vertical green bars illustrate the exons with their respective number above. Narrow green bars illustrate the 5′ and 3′ UTRs. The three known ARID1B domains are indicated by colored lines (blue, LXXLL; brown, ARID; and magenta, BC-Box). The duplication in patient 2 is indicated by a blue bar encompassing exons 5 and 6. The localization of mutations in patients 3–9 is indicated by black lines leading to the mutation identifiers.
Figure 2
Figure 2
Transcript Analysis for the ARID1B Mutations in Patients 2 and 7 (A) Partial sequence electropherograms of ARID1B exon 6 obtained from gDNA and cDNA from patient 2 with a de novo duplication of exons 5 and 6 and his healthy parents. Patient 2 and his father are heterozygous for rs3734441 (c.2172G>A on exon 6) at the gDNA level. Note that the amount of guanine is doubled in the patient. At the cDNA level, the father shows biallelic expression, whereas monoallelic expression of adenine in patient 2 indicates that the duplication leads to a null allele. (B and C) Synonymous variant in the last codon of exon 17 induces exon skipping of exon 17 in patient 7. Using primers located in exons 16 and 18 (c16f and c18r, respectively), indicated by arrows for RT-PCR on RNA from peripheral blood leukocytes, resulted in an additional aberrant product of 148 bp in the patient (lane 3), whereas both parents (lanes 1 and 2) and controls (lanes 4–6) showed only the expected 245 bp fragment (lane 7, genomic DNA control; lane 8, no template control; M, size standard). Exon skipping in the patient was verified by the sequencing of amplified products and is predicted to result in a frameshift and premature stop codon after 76 amino acids (p.Arg1338Argfs∗76). In the patient's lane, an additional third band with a molecular size of ∼310 bp represents a heteroduplex.
Figure 3
Figure 3
Facial Appearance of Patients with Deletions or Mutations in ARID1B Note consistently low-set, posteriorly rotated, and abnormally shaped ears and other frequent dysmorphisms such as frontal bossing, downslanting palpebral fissures, a bulbous nasal tip, and a thin upper lip. (A and B) Patient 1 at age 3 years, 3 months. (C and D) Patient 2 at age 4 years, 11 months. (E and F) Patient 3 at age 3 years, 5 months. (G) Patient 4 at age 5 months. (H and I) Patient 4 at age 7 years, 3 months. (J) Patient 5 at age 4 years, 11 months. (K and L) Patient 5 at age 12 years, 8 months. (M and N) Patient 6 at age 6 years, 3 months. (O and P) Patient 7 at age 3 years, 10 months. (Q and R) Patient 8 at age 17 years.
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