De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome



Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.


By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.


Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.


We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

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Fig. 1: Facial appearance of individuals carrying SMARCA2 variants.
Fig. 2: Schematic representation of SMARCA2 protein and localization of variants associated with Nicolaides–Baraitser syndrome (NCBRS), blepharophimosis intellectual disability syndrome (BIS), and the nonspecific phenotypes.
Fig. 3: Phenotypic effects of SMARCA2 (Snf2) variants in S. cerevisiae.
Fig. 4: Transcriptomic and methylation analyses in individuals harboring SMARCA2 variants.


  1. 1.

    Menke LA, study DDD, Gardeitchik T, et al. Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome. Am J Med Genet A. 2018;176:862–876.

    CAS  PubMed  Google Scholar 

  2. 2.

    Hansen AW, Murugan M, Li H, et al. A genocentric approach to discovery of Mendelian disorders. Am J Hum Genet. 2019;105:974–986.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Karaca E, Posey JE, Coban Akdemir Z, et al. Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med. 2018;20:1528–1537.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum Hered. 2004;58:131–138.

    PubMed  Google Scholar 

  5. 5.

    Hennekam RC, Biesecker LG. Next-generation sequencing demands next-generation phenotyping. Hum Mutat. 2012;33:884–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Nicolaides P, Baraitser M. An unusual syndrome with mental retardation and sparse hair. Clin Dysmorphol. 1993;2:232–236.

    CAS  PubMed  Google Scholar 

  7. 7.

    Sousa SB, Hennekam RC, Nicolaides-Baraitser Syndrome International Consortium. Phenotype and genotype in Nicolaides–Baraitser syndrome. Am J Med Genet C Semin Med Genet. 2014;166C:302–314.

    PubMed  Google Scholar 

  8. 8.

    Van Houdt JK, Nowakowska BA, Sousa SB, et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides–Baraitser syndrome. Nat Genet. 2012;44:445–9, S441.

    PubMed  Google Scholar 

  9. 9.

    Wolff D, Endele S, Azzarello-Burri S, et al. In-frame deletion and missense mutations of the C-Terminal Helicase Domain of SMARCA2 in three patients with Nicolaides–Baraitser syndrome. Mol Syndromol. 2012;2:237–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of pathogenic copy number variation in adults with pediatric-onset epilepsy and intellectual disability. JAMA Neurol. 2017;74:1301–1311.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Sekiguchi F, Tsurusaki Y, Okamoto N, et al. Genetic abnormalities in a large cohort of Coffin–Siris syndrome patients. J Hum Genet. 2019;64:1173–1186.

    CAS  PubMed  Google Scholar 

  12. 12.

    Santen GW, Kriek M, van Attikum H. SWI/SNF complex in disorder: switching from malignancies to intellectual disability. Epigenetics. 2012;7:1219–1224.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Bramswig NC, Ludecke HJ, Alanay Y, et al. Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin–Siris and Nicolaides–Baraitser syndromes. Hum Genet. 2015;134:553–568.

    CAS  PubMed  Google Scholar 

  14. 14.

    Ejaz R, Babul-Hirji R, Chitayat D. The evolving features of Nicolaides–Baraitser syndrome—a clinical report of a 20-year follow-up. Clin Case Rep. 2016;4:351–355.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Tang S, Hughes E, Lascelles K, Euro ERESmaewg, Simpson MA, Pal DK. New SMARCA2 mutation in a patient with Nicolaides–Baraitser syndrome and myoclonic astatic epilepsy. Am J Med Genet A. 2017;173:195–199.

    CAS  PubMed  Google Scholar 

  16. 16.

    Gripp KW, Baker L, Telegrafi A, Monaghan KG. The role of objective facial analysis using FDNA in making diagnoses following whole exome analysis. Report of two patients with mutations in the BAF complex genes. Am J Med Genet A. 2016;170:1754–1762.

    CAS  PubMed  Google Scholar 

  17. 17.

    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.

    CAS  PubMed  Google Scholar 

  18. 18.

    Sanchez AI, Rojas JA. A SMARCA2 mutation in the first case report of Nicolaides–Baraitser syndrome in Latin America: genotype-phenotype correlation. Case Rep Genet. 2017;2017:8639617.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    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.

    CAS  PubMed  Google Scholar 

  20. 20.

    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.

    CAS  PubMed  Google Scholar 

  21. 21.

    Yamamoto T, Imaizumi T, Yamamoto-Shimojima K, et al. Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. Brain Dev. 2019;41:776–782.

    PubMed  Google Scholar 

  22. 22.

    Mari F, Marozza A, Mencarelli MA, et al. Coffin–Siris and Nicolaides–Baraitser syndromes are a common well recognizable cause of intellectual disability. Brain Dev. 2015;37:527–536.

    PubMed  Google Scholar 

  23. 23.

    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;161A:1221–1237.

    PubMed  Google Scholar 

  24. 24.

    Aref-Eshghi E, Bend EG, Hood RL, et al. BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes. Nat Commun. 2018;9:4885.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Shaw WM, Yamauchi H, Mead J, et al. Engineering a model cell for rational tuning of GPCR signaling. Cell. 2019;177:782–96. e727.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gurovich Y, Hanani Y, Bar O, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med. 2019;25:60–64.

    CAS  PubMed  Google Scholar 

  29. 29.

    Li M, Xia X, Tian Y, et al. Mechanism of DNA translocation underlying chromatin remodelling by Snf2. Nature. 2019;567:409–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Mashtalir N, D’Avino AR, Michel BC, et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell. 2018;175:1272–88. e1220.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Schubert HL, Wittmeyer J, Kasten MM, et al. Structure of an actin-related subcomplex of the SWI/SNF chromatin remodeler. Proc Natl Acad Sci U S A. 2013;110:3345–3350.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Han Y, Reyes AA, Malik S, He Y. Cryo-EM structure of SWI/SNF complex bound to a nucleosome. Nature. 2020;579:452–455.

    CAS  Google Scholar 

  33. 33.

    Neigeborn L, Carlson M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics. 1984;108:845–858.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Minard LV, Lin LJ, Schultz MC. SWI/SNF and Asf1 independently promote derepression of the DNA damage response genes under conditions of replication stress. PLoS ONE. 2011;6:e21633.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Chater-Diehl E, Ejaz R, Cytrynbaum C, et al. New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides–Baraitser syndrome. BMC Med Genomics. 2019;12:105.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    van der Sluijs PJ, Jansen S, Vergano SA, et al. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome. Genet Med. 2019;21:1295–1307.

    PubMed  Google Scholar 

  37. 37.

    Krawitz P, Buske O, Zhu N, Brudno M, Robinson PN. The genomic birthday paradox: how much is enough? Hum Mutat. 2015;36:989–997.

    PubMed  Google Scholar 

  38. 38.

    Hoischen A, Krumm N, Eichler EE. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci. 2014;17:764–772.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312:1880–1887.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Vandeweyer G, Helsmoortel C, Van Dijck A, et al. The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism. Am J Med Genet C Semin Med Genet. 2014;166C:315–326.

    PubMed  Google Scholar 

  41. 41.

    Takenouchi T, Miwa T, Sakamoto Y, et al. Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene. Am J Med Genet A. 2017;173:1631–1634.

    CAS  PubMed  Google Scholar 

  42. 42.

    Mandel S, Gozes I. Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J Biol Chem. 2007;282:34448–34456.

    CAS  PubMed  Google Scholar 

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We thank parents of our patients and particularly Anna Caccavo and Charlotte Bull. We thank the Centre de Calcul de l’Université de Bourgogne (CCUB, for technical support and management of information technology platform. This work was supported by Telethon Foundation, Telethon Undiagnosed Diseases Program (TUDP, GSP15001), FEDER, and the Czech Ministry of Health (17-29423A and 00064203 to MH and MH). This work was in part generated within the European Reference Network ITHACA. C.S. is supported by French Medical Foundation (FRM), S.E.K. by French Medical Foundation and French National Research Agency (ANR-10-LABX-49-01 GRAL), J.G. by Finovi and French National Research Agency (ANR-18-CE18-007), and C.D. by Wellcome Trust (209568/Z/17/Z). Patients identified through the Deciphering Developmental Disorders (DDD) Study are reported. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome Trust and Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). Views expressed in this publication are those of the author(s) and not necessarily of Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). Part of the data presented here was provided through access to data and findings generated by the 100,000 Genomes Project, funded by National Institute for Health Research (NIHR) and NHS England (full acknowledgement on

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Correspondence to Jérôme Govin PhD or Antonio Vitobello PhD or Nicola Brunetti-Pierri MD.

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Cappuccio, G., Sayou, C., Tanno, P.L. et al. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome. Genet Med (2020).

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  • Nicolaides–Baraitser syndrome
  • BIS
  • intellectual disability
  • neurodevelopmental disorder