Coffin–Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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Coffin GS, Siris E. Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child. 1960;1970:433–9.
Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012;44:376–8.
Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet. 2012;44:379–80.
Wieczorek D, Bogershausen N, Beleggia F, Steiner-Haldenstatt S, Pohl E, Li Y, 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;22:5121–35.
Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, et al. De novo SOX11 mutations cause Coffin-Siris syndrome. Nat Commun. 2014;5:4011.
Zweier C, Kraus C, Brueton L, Cole T, Degenhardt F, Engels H, et al. A new face of Borjeson-Forssman-Lehmann syndrome? De novo mutations in PHF6 in seven females with a distinct phenotype. J Med Genet. 2013;50:838–47.
Bramswig NC, Caluseriu O, Ludecke HJ, Bolduc FV, Noel NC, Wieland T, et al. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype. Hum Genet. 2017;136:297–305.
Vasileiou G, Vergarajauregui S, Endele S, Popp B, Buttner C, Ekici AB, et al. Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome. Am J Hum Genet. 2018;102:468–79.
The Deciphering Developmental Disorders S, Fitzgerald TW, Gerety SS, Jones WD, van Kogelenberg M, King DA, et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2014;519:223.
Cherot E, Keren B, Dubourg C, Carre W, Fradin M, Lavillaureix A, et al. Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Clin Genet. 2018;93:567–76.
Okamoto N, Ehara E, Tsurusaki Y, Miyake N, Matsumoto N. Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation. Congenit Anom. 2018;58:105–07.
Jahani-Asl A, Cheng C, Zhang C, Bonni A. Pathogenesis of Borjeson–Forssman–Lehmann syndrome: Insights from PHF6 function. Neurobiol Dis. 2016;96:227–35.
Mani U, Sankareswaran AS, Goutham RNA, Mohan SS. SWI/SNF infobase—an exclusive information portal for SWI/SNF remodeling complex subunits. PloS One. 2017;12:e0184445.
Sokpor G, Xie Y, Rosenbusch J, Tuoc T. Chromatin remodeling BAF (SWI/SNF) complexes in neural development and disorders. Front Mol Neurosci. 2017;10:243.
Hota SK, Bruneau BG. ATP-dependent chromatin remodeling during mammalian development. Development. 2016;143:2882–97.
Bevilacqua A, Willis MS, Bultman SJ. SWI/SNF chromatin-remodeling complexes in cardiovascular development and disease. Cardiovascular Pathol. 2014;23:85–91.
Bogershausen N, Wollnik B. Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders. Front Mol Neurosci. 2018;11:252.
Tsurusaki Y, Okamoto N, Ohashi H, Mizuno S, Matsumoto N, Makita Y, et al. Coffin-Siris syndrome is a SWI/SNF complex disorder. Clin Genet. 2014;85:548–54.
Schrier SA, Bodurtha JN, Burton B, Chudley AE, Chiong MA, D’Avanzo MG, et al. The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases. Am J Med Genet Part A. 2012;158A:1865–76.
Vergano SS, Deardorff MA. Clinical features, diagnostic criteria, and management of Coffin-Siris syndrome. Am J Med Genet Part C Semin Med Genet. 2014;166C:252–6.
Campeau PM, Hennekam RC. DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome. Am J Med Genet Part C Semin Med Genet. 2014;166C:327–32.
Van Houdt JK, Nowakowska BA, Sousa SB, van Schaik BD, Seuntjens E, Avonce N, et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides–Baraitser syndrome. Nat Genet. 2012;44:445–9.
Sekiguchi F, Nasiri J, Sedghi M, Salehi M, Hosseinzadeh M, Okamoto N, et al. A novel homozygous DPH1 mutation causes intellectual disability and unique craniofacial features. J Hum Genet. 2018;63:487–91.
Aoi H, Lei M, Mizuguchi T, Nishioka N, Goto T, Miyama S, et al. Nonsense variants in STAG2 result in distinct sex-dependent phenotypes. J Hum Genet. 2019;64:487–92.
Nord AS, Lee M, King MC, Walsh T. Accurate and exact CNV identification from targeted high-throughput sequence data. BMC Genom. 2011;12:184.
Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012;91:597–607.
Al-Shamsi A, Hertecant JL, Souid AK, Al-Jasmi FA. Whole exome sequencing diagnosis of inborn errors of metabolism and other disorders in United Arab Emirates. Orphanet J Rare Dis. 2016;11:94.
Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, et al. Detection of copy number variations in epilepsy using exome data. Clin Genet. 2018;93:577–87.
Bogershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M, et al. Mutation update for kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked kabuki syndrome subtype 2. Hum Mutat. 2016;37:847–64.
Miyake N, Abdel-Salam G, Yamagata T, Eid MM, Osaka H, Okamoto N, et al. Clinical features of SMARCA2 duplication overlap with Coffin-Siris syndrome. Am J Med Genet Part A. 2016;170:2662–70.
Zarate YA, Bhoj E, Kaylor J, Li D, Tsurusaki Y, Miyake N, et al. SMARCE1, a rare cause of Coffin-Siris syndrome: clinical description of three additional cases. Am J Med Genet Part A. 2016;170:1967–73.
Yu Y, Yao R, Wang L, Fan Y, Huang X, Hirschhorn J, et al. De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature. BMC Genom. 2015;16:701.
Mignot C, Moutard ML, Rastetter A, Boutaud L, Heide S, Billette T, et al. ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability. Brain. 2016;139:e64.
Farwell KD, Shahmirzadi L, El-Khechen D, Powis Z, Chao EC, Tippin Davis B, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2014;17:578.
Santen GW, Aten E, Vulto-van Silfhout AT, Pottinger C, van Bon BW, van Minderhout IJ, et al. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat 2013;34:1519–28.
Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, et al. Mutations in PHF6 are associated with Borjeson–Forssman–Lehmann syndrome. Nat Genet. 2002;32:661–5.
Tzschach A, Grasshoff U, Beck-Woedl S, Dufke C, Bauer C, Kehrer M, et al. Next-generation sequencing in X-linked intellectual disability. Eur J Hum Genet. 2015;23:1513–8.
Mangelsdorf M, Chevrier E, Mustonen A, Picketts DJ. Borjeson–Forssman–Lehmann syndrome due to a novel plant homeodomain zinc finger mutation in the PHF6 gene. J child Neurol. 2009;24:610–4.
Sen P, Luo J, Hada A, Hailu SG, Dechassa ML, Persinger J, et al. Loss of Snf5 induces formation of an aberrant SWI/SNF complex. Cell Rep. 2017;18:2135–47.
Holsten T, Bens S, Oyen F, Nemes K, Hasselblatt M, Kordes U, et al. Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis. Eur J Hum Genet. 2018;26:1083–93.
Shibata M, Kanda M, Tanaka H, Umeda S, Miwa T, Shimizu D, et al. Overexpression of Derlin 3 is associated with malignant phenotype of breast cancer cells. Oncol Rep. 2017;38:1760–66.
Prochasson P, Neely KE, Hassan AH, Li B, Workman JL. Targeting activity is required for SWI/SNF function in vivo and is accomplished through two partially redundant activator-interaction domains. Mol Cell. 2003;12:983–90.
Ferreira ME, Prochasson P, Berndt KD, Workman JL, Wright AP. Activator-binding domains of the SWI/SNF chromatin remodeling complex characterized in vitro are required for its recruitment to promoters in vivo. FEBS J. 2009;276:2557–65.
Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, et al. The genetic landscape of Diamond–Blackfan anemia. Am J Hum Genet. 2018;103:930–47.
Sanchis-Juan A, Stephens J, French CE, Gleadall N, Megy K, Penkett C, et al. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing. Genome Med. 2018;10:95.
Miao H, Zhou J, Yang Q, Liang F, Wang D, Ma N, et al. Long-read sequencing identified a causal structural variant in an exome-negative case and enabled preimplantation genetic diagnosis. Hereditas. 2018;155:32.
We thank the patients and their family for participating in this work. We also thank Ms N. Watanabe, Ms K. Takabe and Ms S. Sugimoto for their excellent technical assistance. This work was supported by AMED under the grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, and JP18kk020501 (to NM); JSPS KAKENHI under the grant numbers JP17H01539 (to NM) and JP19H03621 (to NM); grants from the Ministry of Health, Labor, and Welfare (to NM); and the Takeda Science Foundation (to NM and NM). We thank Jeremy Allen, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
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