Abstract
Coffin–Siris Syndrome (CSS, MIM 135900) is a rare genetic disorder, and mutations in ARID1B were recently shown to cause CSS. In this study, we report a novel ARID1B mutation identified by whole-exome sequencing in a patient with clinical features of CSS. We identified a novel heterozygous frameshift mutation c.1584delG in exon 2 of ARID1B (NM_020732.3) predicting a premature stop codon p.(Leu528Phefs*65). Sanger sequencing confirmed the c.1584delG mutation as a de novo in the proband and that it was not present either in her parents, half-sister or half-brother. Clinically, the patient presented with extreme obesity, macrocephaly, hepatomegaly, hyperinsulinism and polycystic ovarian syndrome (PCOS), which have previously not been described in CSS patients. We suggest that obesity, macrocephaly, hepatomegaly and/or PCOS may be added to the list of clinical features of ARID1B mutations, but further clinical reports are required to make a definite conclusion.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Fleck BJ, Pandya A, Vanner L, Kerkering K, Bodurtha J : Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 2001; 99: 1–7.
Coffin GS, Siris E : Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child 1970; 119: 433–439.
Schrier SA, Bodurtha JN, Burton B et al: The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases. Am J Med Genet A 2012; 158A: 1865–1876.
Tsurusaki Y, Okamoto N, Ohashi H et al: Coffin-Siris syndrome is a SWI/SNF complex disorder. Clin Genet 2013, e-pub ahead of print 1 July 2013; doi:10.1111/cge.12225.
Santen GW, Aten E, Sun Y et al: Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 2012; 44: 379–380.
Tsurusaki Y, Okamoto N, Ohashi H et al: Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet 2012; 44: 376–378.
Wieczorek D, Bogershausen N, Beleggia F et al: A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum Mol Genet 2013; 22: 5121–5135.
Hargreaves DC, Crabtree GR : ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res 2011; 21: 396–420.
Santen GW, Aten E, Vulto-van Silfhout AT et al: Coffin-Siris syndrome and the BAF-complex: genotype-phenotype study in 63 patients. Hum mutat 2013; 34: 1519–1528.
Nagamani SC, Erez A, Eng C et al: Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss. Eur J Hum Genet 2009; 17: 573–581.
Halgren C, Kjaergaard S, Bak M et al: Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin Genet 2012; 82: 248–255.
Hoyer J, Ekici AB, Endele S et al: Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am J Hum Genet 2012; 90: 565–572.
Michelson M, Ben-Sasson A, Vinkler C et al: Delineation of the interstitial 6q25 microdeletion syndrome: refinement of the critical causative region. Am J Med Genet A 2012; 158A: 1395–1399.
Kosho T, Okamoto N, Ohashi H et al: Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature. Am J Med Genet A 2013; 161: 1221–1237.
Azziz R : Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006; 91: 781–785.
Vaher U, Noukas M, Nikopensius T et al: De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders. J Child Neurol 2013, e-pub ahead of print 18 December 2013.
Ronan JL, Wu W, Crabtree GR : From neural development to cognition: unexpected roles for chromatin. Nat Rev Genet 2013; 14: 347–359.
Franks S : Polycystic ovary syndrome. N Engl J Med 1995; 333: 853–861.
Acknowledgements
This work was supported by the Estonian Science Foundation (grant no. 8175), targeted Financing from the Estonian Ministry of Education and Research (grant no. SF0180142s08), the EU FP7 (grant no 313010), the Development Fund of the University of Tartu (grant no. SP1GVARENG) and the European Regional Development Fund to the Center of Excellence in Genomics (EXCEGEN; grant no 3.2.0304.11-0312).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Vals, MA., Õiglane-Shlik, E., Nõukas, M. et al. Coffin–Siris Syndrome with obesity, macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene. Eur J Hum Genet 22, 1327–1329 (2014). https://doi.org/10.1038/ejhg.2014.25
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2014.25
