The ARID1B Spectrum in 143 Patients: from Nonsyndromic Intellectual Disability to Coffin-Siris Syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

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References

Malli T, Duba H, Erdel M, Marschon R, Kranewitter W, Deutschbauer S . Disruption of the ARID1B and ADAMTS6 loci due to a t(5;6)(q12.3;q25.3) in a patient with developmental delay. Am J Med Genet A. 2014; 164A(12):3126-31. DOI: 10.1002/ajmg.a.36738. View

Yu Y, Yao R, Wang L, Fan Y, Huang X, Hirschhorn J . De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature. BMC Genomics. 2015; 16:701. PMC: 4574214. DOI: 10.1186/s12864-015-1898-1. View

Seabra C, Szoko N, Erdin S, Ragavendran A, Stortchevoi A, Maciel P . A novel microduplication of ARID1B: Clinical, genetic, and proteomic findings. Am J Med Genet A. 2017; 173(9):2478-2484. PMC: 5561488. DOI: 10.1002/ajmg.a.38327. View

Trujillano D, Bertoli-Avella A, Kandaswamy K, Weiss M, Koster J, Marais A . Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet. 2016; 25(2):176-182. PMC: 5255946. DOI: 10.1038/ejhg.2016.146. View

Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y . Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012; 44(4):376-8. DOI: 10.1038/ng.2219. View

Sonmez F, Uctepe E, Gunduz M, Gormez Z, Erpolat S, Oznur M . Coffin-Siris syndrome with café-au-lait spots, obesity and hyperinsulinism caused by a mutation in the ARID1B gene. Intractable Rare Dis Res. 2016; 5(3):222-6. PMC: 4995424. DOI: 10.5582/irdr.2014.01040. View

Nord A, Roeb W, Dickel D, Walsh T, Kusenda M, OConnor K . Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur J Hum Genet. 2011; 19(6):727-31. PMC: 3110052. DOI: 10.1038/ejhg.2011.24. View

Sim J, White S, Fitzpatrick E, Wilson G, Gillies G, Pope K . Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency. Orphanet J Rare Dis. 2014; 9:43. PMC: 4022252. DOI: 10.1186/1750-1172-9-43. View

Santen G, Aten E, Vulto-van Silfhout A, Pottinger C, van Bon B, van Minderhout I . Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat. 2013; 34(11):1519-28. DOI: 10.1002/humu.22394. View

10.

Santen G, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M . Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet. 2012; 44(4):379-80. DOI: 10.1038/ng.2217. View

11.

Wright C, Fitzgerald T, Jones W, Clayton S, McRae J, van Kogelenberg M . Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2014; 385(9975):1305-14. PMC: 4392068. DOI: 10.1016/S0140-6736(14)61705-0. View

12.

Hoyer J, Ekici A, Endele S, Popp B, Zweier C, Wiesener A . 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(3):565-72. PMC: 3309205. DOI: 10.1016/j.ajhg.2012.02.007. View

13.

Halgren C, Kjaergaard S, Bak M, Hansen C, El-Schich Z, Anderson C . Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin Genet. 2011; 82(3):248-55. PMC: 3464360. DOI: 10.1111/j.1399-0004.2011.01755.x. View

14.

Tsurusaki Y, Okamoto N, Ohashi H, Mizuno S, Makita Y, Fukuda M . Coffin-Siris syndrome is a SWI/SNF complex disorder. Clin Genet. 2013; 85(6):548-54. DOI: 10.1111/cge.12225. View

15.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

16.

Girdea M, Dumitriu S, Fiume M, Bowdin S, Boycott K, Chenier S . PhenoTips: patient phenotyping software for clinical and research use. Hum Mutat. 2013; 34(8):1057-65. DOI: 10.1002/humu.22347. View

17.

Mignot C, Moutard M, Rastetter A, Boutaud L, Heide S, Billette T . ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability. Brain. 2016; 139(11):e64. DOI: 10.1093/brain/aww181. View

18.

Vengoechea J, Carpenter L, Zarate Y . Papillary thyroid cancer in a patient with interstitial 6q25 deletion including ARID1B. Am J Med Genet A. 2014; 164A(7):1857-9. DOI: 10.1002/ajmg.a.36515. View

19.

Mari F, Marozza A, Mencarelli M, Lo Rizzo C, Fallerini C, Dosa L . Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability. Brain Dev. 2014; 37(5):527-36. DOI: 10.1016/j.braindev.2014.08.009. View

20.

Ben-Salem S, Sobreira N, Akawi N, Al-Shamsi A, John A, Pramathan T . Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings. Am J Med Genet A. 2015; 170A(1):156-61. PMC: 5448135. DOI: 10.1002/ajmg.a.37405. View