Sim, J. C. H.2; White, S. M.2; Fitzpatrick, E.2; Wilson, G. R.2; Gillies, G.2; Pope, K.2; Mountford, H. S.2; Tørring, Pernille M.4; McKee, S.2; Vulto-van Silfhout, A. T.2; Jhangiani, S. N.2; Muzny, D. M.2; Leventer, R. J.2; Delatycki, M. B.2; Amor, D. J.2; Lockhart, P. J.2
1 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Oto-rhino-laryngologi, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU4 Oto-rhino-laryngologi, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
Background: 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. Methods/results: 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 S-1 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. Conclusions: 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.