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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Joe C H Sim, Susan M White, Elizabeth Fitzpatrick, Gabrielle R Wilson, Greta Gillies, Kate Pope, Hayley S Mountford, Pernille M Torring, Shane McKee, Anneke T Vulto-van Silfhout, Shalini N Jhangiani, Donna M Muzny, Richard J Leventer, Martin B Delatycki, David J Amor, Paul J Lockhart
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Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-43) contains supplementary material, which is available to authorized users.
Joe C H Sim, Susan M White contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

JS performed molecular analysis and co-wrote the manuscript. SW provided and interpreted the clinical data and co-wrote the manuscript. EF, GW, GG, HM, SJ and DM performed molecular analysis and interpreted data. KP performed patient recruitment and read/contributed to the manuscript. PT, ATVvS, SM, RJL, MBD and DJA provided and interpreted the clinical data and revised the manuscript. PJL collected and analysed the data, wrote the manuscript and is responsible for overall content as guarantor and corresponding author.



Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism.


High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient’s distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them.


This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.
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