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Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

2018; Elsevier BV; Volume: 104; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2018.11.007

ISSN

1537-6605

Autores

Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas X. Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong‐hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather M. McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martı́nez, Alfonso Caro‐Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan‐Khetarpal, Sonal Desai, Sakkubai Naidu, Julien Thévenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer Tarpinian, Jill A. Rosenfeld, Brendan Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David Bick, Camille L. Birch, Devon Bonner, Braden Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell‐Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos R. Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine Groden, Andrea Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Yong‐hui Jiang, Jean M. Johnston, Angela Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Brendan Lee, Hane Lee, Shawn Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julián A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie‐Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Peña, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer Valivullah, Éric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Sophie Nicole, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng,

Tópico(s)

Genomic variations and chromosomal abnormalities

Resumo

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits. SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits. The chromatin-remodeling complex BRG1-associated factor (BAF) plays an essential role in the regulation of gene expression and higher-order chromatin organization by modulating the nucleosome and changing chromatin conformation and accessibility.1Barutcu A.R. Lajoie B.R. Fritz A.J. McCord R.P. Nickerson J.A. van Wijnen A.J. Lian J.B. Stein J.L. Dekker J. Stein G.S. Imbalzano A.N. SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells.Genome Res. 2016; 26: 1188-1201Crossref PubMed Scopus (65) Google Scholar, 2Ronan J.L. Wu W. Crabtree G.R. From neural development to cognition: unexpected roles for chromatin.Nat. Rev. Genet. 2013; 14: 347-359Crossref PubMed Scopus (338) Google Scholar BAFopathies are a heterogeneous group of disorders caused by mutations in the various subunits composing the BAF complex. The clinical phenotypic spectrum of BAFopathies is wide and involves various human neurodevelopmental disorders including syndromic and nonsyndromic intellectual disability (ID), growth retardation,3Santen G.W. Aten E. Vulto-van Silfhout A.T. Pottinger C. van Bon B.W. van Minderhout I.J. Snowdowne R. van der Lans C.A. Boogaard M. Linssen M.M. et al.Coffin-Siris consortiumCoffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.Hum. Mutat. 2013; 34: 1519-1528Crossref PubMed Scopus (140) Google Scholar, 4Kosho T. Okamoto N. Coffin-Siris Syndrome International CollaboratorsGenotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.Am. J. Med. Genet. C. Semin. Med. Genet. 2014; 166C: 262-275Crossref PubMed Scopus (100) Google Scholar, 5Sousa S.B. Hennekam R.C. Nicolaides-Baraitser Syndrome International ConsortiumPhenotype and genotype in Nicolaides-Baraitser syndrome.Am. J. Med. Genet. C. Semin. Med. 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Genet. 2012; 44 (S441): 445-449Crossref PubMed Scopus (179) Google Scholar, 9Vandeweyer G. Helsmoortel C. Van Dijck A. Vulto-van Silfhout A.T. Coe B.P. Bernier R. Gerdts J. Rooms L. van den Ende J. Bakshi M. et al.The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism.Am. J. Med. Genet. C. Semin. Med. Genet. 2014; 166C: 315-326Crossref PubMed Scopus (58) Google Scholar, 10Santen G.W. Kriek M. van Attikum H. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability.Epigenetics. 2012; 7: 1219-1224Crossref PubMed Scopus (61) Google Scholar sporadic autism,11Neale B.M. Kou Y. Liu L. Ma'ayan A. Samocha K.E. Sabo A. Lin C.F. Stevens C. Wang L.S. Makarov V. et al.Patterns and rates of exonic de novo mutations in autism spectrum disorders.Nature. 2012; 485: 242-245Crossref PubMed Scopus (1275) Google Scholar schizophrenia,12Loe-Mie Y. Lepagnol-Bestel A.M. Maussion G. Doron-Faigenboim A. Imbeaud S. Delacroix H. Aggerbeck L. Pupko T. Gorwood P. Simonneau M. Moalic J.M. SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.Hum. Mol. Genet. 2010; 19: 2841-2857Crossref PubMed Scopus (70) Google Scholar and amyotrophic lateral sclerosis.13Chesi A. Staahl B.T. Jovičić A. Couthouis J. Fasolino M. Raphael A.R. Yamazaki T. Elias L. Polak M. Kelly C. et al.Exome sequencing to identify de novo mutations in sporadic ALS trios.Nat. Neurosci. 2013; 16: 851-855Crossref PubMed Scopus (115) Google Scholar The most recognizable syndrome associated with BAF abnormalities is Coffin-Siris syndrome (CSS [MIM: 135900]). This is a genetically heterogeneous ID syndrome characterized by developmental delay (DD), speech delay, coarse facial appearance, feeding difficulties, and hypoplastic-to-absent fifth finger nails and fifth distal phalanges.14Schrier S.A. Bodurtha J.N. Burton B. Chudley A.E. Chiong M.A. D'avanzo M.G. Lynch S.A. Musio A. Nyazov D.M. Sanchez-Lara P.A. et al.The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases.Am. J. Med. Genet. A. 2012; 158A: 1865-1876Crossref PubMed Scopus (62) Google Scholar This syndrome is associated with abnormalities in multiple subunits of the BAF complex including the ATPase subunit SMARCA4 (MIM: 603254), the common core subunit SMARCB1 (MIM: 601607), and BAF accessory subunits such as SMARCE1/BAF57 (MIM: 603111), ARID1A (MIM: 603024), ARID1B (MIM: 614556),15Tsurusaki Y. Okamoto N. Ohashi H. Kosho T. Imai Y. Hibi-Ko Y. Kaname T. Naritomi K. Kawame H. Wakui K. et al.Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.Nat. Genet. 2012; 44: 376-378Crossref PubMed Scopus (372) Google Scholar ARID2 (MIM: 609539),16Bramswig N.C. Caluseriu O. Lüdecke H.J. Bolduc F.V. Noel N.C. Wieland T. Surowy H.M. Christen H.J. Engels H. Strom T.M. Wieczorek D. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.Hum. Genet. 2017; 136: 297-305Crossref PubMed Scopus (41) Google Scholar and DPF2 (MIM: 601671).17Vasileiou G. Vergarajauregui S. Endele S. Popp B. Büttner C. Ekici A.B. Gerard M. Bramswig N.C. Albrecht B. Clayton-Smith J. et al.Deciphering Developmental Disorders StudyMutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome.Am. J. Hum. Genet. 2018; 102: 468-479Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar CSS can result of pathogenic changes in other chromatin remodeling proteins with no direct interaction with BAF complex, including SOX11 (MIM: 600898)18Hempel A. Pagnamenta A.T. Blyth M. Mansour S. McConnell V. Kou I. Ikegawa S. Tsurusaki Y. Matsumoto N. Lo-Castro A. et al.DDD CollaborationDeletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.J. Med. Genet. 2016; 53: 152-162Crossref PubMed Scopus (52) Google Scholar and PHF6 (MIM: 300414).19Zweier C. Rittinger O. Bader I. Berland S. Cole T. Degenhardt F. Di Donato N. Graul-Neumann L. Hoyer J. Lynch S.A. et al.Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome.Am. J. Med. Genet. C. Semin. Med. Genet. 2014; 166C: 290-301Crossref PubMed Scopus (22) Google Scholar Other BAFopathies include Nicolaides-Baraitser syndrome (MIM: 601358) caused by pathogenic variants in SMARCA2 (MIM: 600014) that has a significant phenotypic overlap with CSS and is characterized by ID, sparse hair, short stature, microcephaly, brachydactyly, interphalangeal joint swellings, and epilepsy.20Nicolaides P. Baraitser M. An unusual syndrome with mental retardation and sparse hair.Clin. Dysmorphol. 1993; 2: 232-236Crossref PubMed Google Scholar, 21Pretegiani E. Mari F. Renieri A. Penco S. Dotti M.T. Nicolaides-Baraitser syndrome: defining a phenotype.J. Neurol. 2016; 263: 1659-1660Crossref PubMed Scopus (4) Google Scholar Some individuals with clinical diagnosis of DOORS syndrome (MIM: 220500), characterized by deafness, onychodystrophy, osteodystrophy, ID, and seizures, were found to carry pathogenic variants in SMARCB1 (MIM: 601607), highlighting the clinical overlap between CSS and DOORS syndrome.22Campeau P.M. Hennekam R.C. DOORS syndrome collaborative groupDOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome.Am. J. Med. Genet. C. Semin. Med. Genet. 2014; 166C: 327-332Crossref PubMed Scopus (33) Google Scholar We have previously reported mutations in another BAF subunit, ACTL6A (MIM: 604958), to be associated with ID.23Marom R. Jain M. Burrage L.C. Song I.W. Graham B.H. Brown C.W. Stevens S.J.C. Stegmann A.P.A. Gunter A.T. Kaplan J.D. et al.Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.Hum. Mutat. 2017; 38: 1365-1371Crossref PubMed Scopus (18) Google Scholar Pathogenic variants in ADNP (MIM: 611386), encoding a transcription factor that interacts with the BAF complex, have been identified in individuals presenting dysmorphic facial features, autism spectrum disorder (ASD), ID, hypotonia, and congenital heart defects.24Helsmoortel C. Vulto-van Silfhout A.T. Coe B.P. Vandeweyer G. Rooms L. van den Ende J. Schuurs-Hoeijmakers J.H. Marcelis C.L. Willemsen M.H. Vissers L.E. et al.A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.Nat. Genet. 2014; 46: 380-384Crossref PubMed Scopus (216) Google Scholar Detailed phenotypic and genetic comparison between the different BAF-related syndromes has been discussed elsewhere.4Kosho T. Okamoto N. Coffin-Siris Syndrome International CollaboratorsGenotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.Am. J. Med. Genet. C. Semin. Med. Genet. 2014; 166C: 262-275Crossref PubMed Scopus (100) Google Scholar, 25Bögershausen N. Wollnik B. Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders.Front. Mol. Neurosci. 2018; 11: 252Crossref PubMed Scopus (71) Google Scholar SMARCC2 (MIM: 601734) encodes BAF170, a common core subunit of the BAF complexes with high homology to SMARCC1 (BAF155).26Ring H.Z. Vameghi-Meyers V. Wang W. Crabtree G.R. Francke U. Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome.Genomics. 1998; 51: 140-143Crossref PubMed Scopus (36) Google Scholar It is an intrinsic factor of glial radial cells and plays a crucial role in embryogenesis and corticogenesis, determining the mammalian body and cortical size.27Tuoc T.C. Boretius S. Sansom S.N. Pitulescu M.E. Frahm J. Livesey F.J. Stoykova A. Chromatin regulation by BAF170 controls cerebral cortical size and thickness.Dev. Cell. 2013; 25: 256-269Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Smarcc2;Smarcc1 double knockout mice demonstrated proteasome-mediated degradation of the entire BAF complexes, resulting in impairment of the global epigenetic and gene expression program of forebrain development.28Narayanan R. Pirouz M. Kerimoglu C. Pham L. Wagener R.J. Kiszka K.A. Rosenbusch J. Seong R.H. Kessel M. Fischer A. et al.Loss of BAF (mSWI/SNF) complexes causes global transcriptional and chromatin state changes in forebrain development.Cell Rep. 2015; 13: 1842-1854Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Recently, deletion of Smarcc2 in mice revealed its role in learning and behavioral adaptation.29Tuoc T. Dere E. Radyushkin K. Pham L. Nguyen H. Tonchev A.B. Sun G. Ronnenberg A. Shi Y. Staiger J.F. et al.Ablation of BAF170 in developing and postnatal dentate gyrus affects neural stem cell proliferation, differentiation, and learning.Mol. Neurobiol. 2017; 54: 4618-4635Crossref PubMed Scopus (27) Google Scholar SMARCC2 was also reported as one of the chromatin-remodeling genes involved in ASD.30Ben-David E. Shifman S. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism.Mol. Psychiatry. 2013; 18: 1054-1056Crossref PubMed Scopus (102) Google Scholar Despite its significant biological role, variants in SMARCC2 have not been directly associated with a syndrome in humans previously. We report 15 unrelated individuals (Tables 1 and S1) with variants in SMARCC2, detected by whole-exome sequencing (WES), and with clinical presentation that includes mild to severe ID (HP:0012736), DD with prominent speech delay (HP:0000750), behavioral abnormalities (HP:0000708), growth retardation (HP:0008897), feeding difficulties at the neonatal period (HP:0008872), hypotonia (HP:0011398), and dysmorphic features including hypertrichosis (HP:0000998), thick eyebrows (HP:0000574)/prominent supra-orbital ridges (HP:0000336), and thin upper and lower vermillion (HP:0000233), suggesting overlap with Coffin-Siris and Nicolaides-Baraitser syndromes. Subjects in this cohort were gathered using GeneMatcher.31Sobreira 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: 928-930Crossref PubMed Scopus (821) Google Scholar All individuals' families from the different institutions agreed to participate in this study and signed appropriate consent forms. Permission for clinical photographs was given separately. Individual 4 has been reported before and was identified in a gene panel screening (1,256 genes) of 96 individuals with ID.32Martínez F. Caro-Llopis A. Roselló M. Oltra S. Mayo S. Monfort S. Orellana C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.J. Med. Genet. 2017; 54: 87-92Crossref PubMed Scopus (83) Google Scholar The variant c.1833+2T>C in individual 10 was reported before as part of a work to identify new gene-disease associations in trio WES from 119 undiagnosed individuals.33Zhu X. Petrovski S. Xie P. Ruzzo E.K. Lu Y.F. McSweeney K.M. Ben-Zeev B. Nissenkorn A. Anikster Y. Oz-Levi D. et al.Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.Genet. Med. 2015; 17: 774-781Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar Individuals 1, 4, 6, 7, 9–13, and 15 had trio WES. Individuals 2, 3, 5, and 14 had a proband WES followed by Sanger confirmation for the individual and parents. Biological parents of individuals 3 and father of individual 8 are not available for testing. Individual 8 had duo WES with his mother and results were re-analyzed as part of the Undiagnosed Diseases Network (UDN). This individual was found to harbor an intronic splice site variant c.1833+1G>T in SMARCC2 that was not found in his mother. Twelve of the fifteen individuals have proven de novo variants in SMARCC2. Individual 2 inherited the variant from his affected father. Paternal grandparents were negative for the variant indicating a de novo variant in the father.Table 1Summary of SMARCC2 Variants and Clinical Presentation of 15 IndividualsIndividual ## 1# 2# 3# 4aSee Martínez et al.32# 5# 6# 7# 8# 9# 10bSee Zhu et al.33# 11# 12# 13# 14# 15TotalGenderMMMFMFMMMMMFMMMAge (Y)5 Y3 Y2 Y17 Y4 Y18 Y11 Y11 Y2.5 Y10.5 Y19 Y7 Y8 Y5 Y27 MoNucleotide changec.400A>Gc.723G>Ac.999dupAc.1311−3C>Gc.1826T>Cc.1829T>Cc.1829T>Cc.1833+1G>Tc.1833+2T>Cc.1833+2T>Cc.1838T>Cc.1903T>Cc.2686A>Gc.2699A>Gc.3456_3458delCATAmino acid changep.Asn134Aspp.Trp241∗p.Glu334Argfs∗49splicing variantp.Leu609Prop.Leu610Prop.Leu610Prosplicing variantcSee Figure 3.splicing variantsplicing variantp.Leu613Prop.Cys635Argp.Met896Valp.Glu900Glyp.Met1153delDe novo variant?yesno (affected father)n/ayesyesyesyesn/ayesyesyesyesyesyesyesAffected domainSMARCC_NSMARCC_NSMARCC_NSWIRMSANTSANTSANTSANTSANTSANTSANTSANTSMARCC_CSMARCC_Ccarboxy terminalNeurodevelopmental AbnormalitiesDevelopmental delay and/or intellectual disabilitymild DDmild DDmild DDsevere DDsevere DDsevere DDsevere DDsevere DD (DQ=20)moderate IDmoderate DD, moderate-severe IDmoderate-severe DDmoderate DD, moderate IDmoderate-severe DDmild IDmild DD15/15Speech impairment−speech delay−absence of languageabsence of languageabsence of languageabsence of languageabsence of languageabsence of languageminimal speechabsence of languagespeech delayspeech delayspeech delayspeech abnormalities13/15Behavioral abnormalities−++++−++−−−++++10/15Hypotonia+spasticity+++ and spasticity+++++−++++13/15Seizures−−−++−+−−−+−−−−4/15Movement disorder−+−−−+−−−−−−−−−2/15CNS abnormalities on MRIn/atwo discrete hyperintens white matter lesionsn/anormal MRIthinning of corpus callosum and splenium, periventricular white matter lossgeneralized cerebral atrophy, hypointensity globus pallidusgeneralized cerebral atrophy, hypo-myelinationnormal MRInormal MRInormal MRIabnormal corpus callosumslightly small corpus callosum, prominent perivascular spacesnormal MRInormal MRIn/a6/12GrowthFTT−−−−+++−++−−−+−6/15Sucking/feeding difficulty−−−−+++−+++−−++8/15Craniofacial Features11/15Thin/sparse scalp hair−−−−++−−+−+−−−−4/15Hypertrichosis−−−++−−−+−−+++−6/15Thick eyebrows−−−+−++−+−+−−+−6/15Long eyelashes−−−−−−−−+++−++−5/15Ptosis−−−−−++−−++−−+−5/15Thin upper lip vermilion−−−−++−++−−++−−6/15Thick lower lip vermilion−−−+−−+−+−+−+−−5/15Palate abnormalities−−−−−−−−−++−−+−3/15Nose upturned/anteverted nostrils−−−−+++−−+++−−−6/15Skeletal-Limb Features5th finger or toe/nails abnormalities−−−−+−−−−++−−+−4/15Scoliosis−−−kyphosis+++−−−−+−−−5/15OtherCardiovascularn/a−−−n/aleft coronary distensionnon-progressive mild aortic dilatation (Z score=2.54).−−−−−n/a−n/a2/11Inguinal hernia−−−−+−++−−−−−−−3/15Undescended testisn/a−−n/ap+n/ap+−n/a−−n/ap−−n/a2/12Skin problems−hypo pigmented hair, cafe au lait macules−−eczemaeczema, scleroderma−−hypo-melanotic maculavitiligo (present in unaffected father)hyper pigmented irregular skin on backeczema−−−7/15Abbreviations: FTT, failure to thrive; DD, developmental delay; ID, intellectual disability; DQ, developmental quotient; CNS, central nervous system; MRI, magnetic resonance imaging; M, male; F, female; Y, years; Mo, months; n/a, not available information; n/ap, not applicable. Minus sign (−), not reported in this individual; plus sign (+), reported in this individual.a See Martínez et al.32Martínez F. Caro-Llopis A. Roselló M. Oltra S. Mayo S. Monfort S. Orellana C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.J. Med. Genet. 2017; 54: 87-92Crossref PubMed Scopus (83) Google Scholarb See Zhu et al.33Zhu X. Petrovski S. Xie P. Ruzzo E.K. Lu Y.F. McSweeney K.M. Ben-Zeev B. Nissenkorn A. Anikster Y. Oz-Levi D. et al.Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.Genet. Med. 2015; 17: 774-781Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholarc See Figure 3. Open table in a new tab Abbreviations: FTT, failure to thrive; DD, developmental delay; ID, intellectual disability; DQ, developmental quotient; CNS, central nervous system; MRI, magnetic resonance imaging; M, male; F, female; Y, years; Mo, months; n/a, not available information; n/ap, not applicable. Minus sign (−), not reported in this individual; plus sign (+), reported in this individual. All of the individuals presented here have some degree of ID and/or DD (Tables 1 and S1). Ten (10/15, 65%) have moderate to profound DD and ID while the other five individuals have only mild ID or mild DD. 13/15 (86%) individuals have speech impairment with 7 of them completely lacking language. Most individuals present muscle tone abnormalities. 13/15 (85%) individuals present significant hypotonia, while two of the individuals present high tone or spasticity. Ten of the individuals (67%) present behavioral problems including aggression and self-injurious behavior as well as hyperactivity, hypersensitivity to touch, sleep disturbances, and obsessive and rigid behavior. Two were noted to have difficulties in social interactions, yet not qualified for formal diagnosis of autism. Eight individuals present feeding difficulties and six of them have mostly postnatal growth retardation. Individual 9 has continuous feeding difficulties with laryngomalacia and nasal feeding tube since age 14 months. 11 out of the 15 individuals are reported to have dysmorphic craniofacial features (Figure 1). The most pronounced dysmorphic features are hypertrichosis (6/15), thick eyebrows/prominent supra-orbital ridges (6/15), thin upper or thick lower lip-vermilion (6/15 and 5/15, respectively), and upturned nose (6/15). Most of the individuals have normal fifth finger/toe and finger/toenail. 8 of the 15 individuals presented here (1, 5–7, 11–14) have one of seven missense variants in SMARCC2 (GeneBank: NM_003075.3) and all are predicted to be deleterious/probably damaging according to PROVEAN and SIFT, in silico tools to predict the functional effect of an amino acid substitution. All missense variants are in well-conserved amino acids in SMARCC2 (Figure 2). In vitro missense tolerance ratio (MTR) tool shows that six of the seven missense variants presented here preferentially affect one of the 25% most intolerant residues of SMARCC2 (p = 0.0004) with p.Asn134Asp being the only missense variant affecting a tolerant region of this gene (Figure S1). This might be consistent with the milder phenotype presented in this individual. SMARCC2 ExAC z-score for intolerance for missense variations is significantly high (4.26) and the gene is predicted to be potentially associated with dominant conditions according to an LDA score of 2.435 by the DOMINO algorithm.34Quinodoz M. Royer-Bertrand B. Cisarova K. Di Gioia S.A. Superti-Furga A. Rivolta C. DOMINO: using machine learning to predict genes associated with dominant disorders.Am. J. Hum. Genet. 2017; 101: 623-629Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Individual 15 harbors a de novo in-frame deletion of methionine 1153 (c.3456_3458delCAT). Methionine 1153 deletion and its missense substitutions to various amino acids (isoleucine, threonine, valine) appear once (allele frequency 3.231 × 10−5) and four times, respectively, in gnomAD.35Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O'Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar This might indicate that this position is relatively tolerable for changes and explain the mild clinical presentation of individual 15. It is important to note that detailed phenotype such as IQ scores are not available for individuals included in the ExAC database. Individuals 2 and 3 carry truncating mutations located at the N terminus of SMARCC2 (exons 9 and 11). Individual 2 carries a heterozygous nonsense variant (p.Trp241∗) and individual 3 carries a frameshift variant (p.Glu334Argfs∗49). Interestingly, both present mild phenotype. Individual 2, who presents mainly behavioral abnormalities and only mild DD, inherited the change from his affected father who presents with borderline intelligence (IQ of 72) and behavior problems. ExAC database identified only a single loss-of-function allele in SMARCC2 (p.Glu389Aspfs∗5); however, with only 11 (22%) of 49 reads at this frameshift variant site, it is unlikely to be a germline variant (binomial exact test for 50% germline heterozygous expectation; p = 0.0001). The depletion of protein-truncating variants in SMARCC2 is evident in large human population reference cohorts. Based on the ExAC cohort, SMARCC2 achieves a LoF depletion FDR adjusted p = 5.5 × 10−11, ranking it among the 1.6% most significantly LoF-depleted genes in the human exome.36Petrovski S. Gussow A.B. Wang Q. Halvorsen M. Han Y. Weir W.H. Allen A.S. Goldstein D.B. The intolerance of regulatory sequence to genetic variation predicts gene dosage sensitivity.PLoS Genet. 2015; 11: e1005492Crossref PubMed Scopus (79) Google Scholar It also has a probability of loss-of-function (LoF) intolerance (pLI) score of 1, supporting deleterious effect for predicted LoF pathogenic variants.35Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O'Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar SMARCC2%HI score of 20.29 also predicts that this gene is less likely to tolerate a loss-of-function variant or deletion.37Huang N. Lee I. Marcotte E.M. Hurles M.E. Characterising and predicting haploinsufficiency in the human genome.PLoS Genet. 2010; 6: e1001154Crossref PubMed Scopus (445) Google Scholar Four individuals harbor splicing variants. Three individuals (8–10) have one of two variants in intron 19 (c.1833+2T>C and c.1833+1G>T) that are predicted in silico to affect splicing donor site according to Human Splicing Finder (HSF). One individual (4) presents a splicing variant in intron 14 (c.1311−3C>G) that is predicted to affect exon acceptor site. In vitro assay in lymphocytes from individual 8 (c.1833+1G>T) indicates that this variant leads to abnormal splicing with deletion of exon 19 (amino acids 590–611) that compose the SANT domain in SMARCC2 (Figure 3A). The capture of a shorter cDNA product using RT-PCR might indicate the presence of an mRNA escaping nonsense-mediated decay (NMD). RT-qPCR quantification of SMARCC2 in lymphocytes from individual 4 (c.1311−3C>G) demonstrates a ∼50% decrease in mRNA compared to a control and a coding in-frame deletion (individual 15, p.Met1153del), suggesting haploinsufficiency through NMD (Figure 3B). Nine individuals carry missense or splicing variants in the highly conserved SWIRM (Swi3, Rsc8, and Moira) and SANT (Swi3, Ada2, NCoR, and TFIIIB) domains of SMARCC2 (Figure 2). The SWIRM domain interacts with DNA, binds di-nucleosome structures, and mediates specific protein-protein interactions.38Aravind L. Iyer L.M. The SWIRM domain: a conserved module found in chromosomal proteins points to novel chromatin-modifying activities.Genome Biol 3. 2002; (RESEARCH0039)Crossref Google Scholar The SANT domain has DNA-binding activity39Yoneyama M. Tochio N. Umehara T. Koshiba S. Inoue M. Yabuki T. Aoki M. Seki E. Matsuda T. Watanabe S. et al.Structural and functional differences of SWIRM domain subtypes.J. Mol. Biol. 2007; 369: 222-238Crossref PubMed Scopus (35) Google Scholar and is believed to function as a histone tail binding module.40Boyer L.A. Latek R.R. Peterson C.L. The SANT domain: a uniq

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