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De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism

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Abstract

SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4). Here, we describe two unrelated individuals with de novo variants in SETD1B identified by trio-based whole exome sequencing: c.5524C>T, p.(Arg1842Trp) and c.5575C>T, p.(Arg1859Cy). The two missense variants occurred at evolutionarily conserved amino acids and are located within the SET domain, which plays a pivotal role in catalyzing histone methylation. Previous studies have suggested that de novo microdeletions in the 12q24.3 region encompassing SETD1B were associated with developmental delays, intellectual disabilities, autism/autistic behavior, large stature and craniofacial anomalies. Comparative mapping of 12q24.3 deletions refined the candidate locus, indicating KDM2B and SETD1B to be the most plausible candidate genes for the pathogenicity of 12q24.3 deletion syndrome. Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions. Therefore, our study suggests that SETD1B aberration is likely to be the core defect in 12q24.3 deletion syndrome.

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References

  • Baple E, Palmer R, Hennekam RC (2010) A microdeletion at 12q24.31 can mimic Beckwith–Wiedemann syndrome neonatally. Mol Syndromol 1:42–45. https://doi.org/10.1159/000275671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bledau AS, Schmidt K, Neumann K, Hill U, Ciotta G, Gupta A, Torres DC, Fu J, Kranz A, Stewart AF, Anastassiadis K (2014) The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation. Development 141:1022–1035. https://doi.org/10.1242/dev.098152

    Article  CAS  PubMed  Google Scholar 

  • Choi YJ, Oh HR, Choi MR, Gwak M, An CH, Chung YJ, Yoo NJ, Lee SH (2014) Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability. Hum Pathol 45:1674–1681. https://doi.org/10.1016/j.humpath.2014.04.013

    Article  CAS  PubMed  Google Scholar 

  • de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929. https://doi.org/10.1056/NEJMoa1206524

    Article  PubMed  Google Scholar 

  • Deciphering Developmental Disorders S (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature 542:433–438. https://doi.org/10.1038/nature21062

    Article  Google Scholar 

  • Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, Handsaker RE, McCarroll SA, O’Donovan MC, Owen MJ, Kirov G, Sullivan PF, Hultman CM, Sklar P, Purcell SM (2012) Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet 91:597–607. https://doi.org/10.1016/j.ajhg.2012.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukai R, Saitsu H, Tsurusaki Y, Sakai Y, Haginoya K, Takahashi K, Hubshman MW, Okamoto N, Nakashima M, Tanaka F, Miyake N, Matsumoto N (2016) De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures. J Hum Genet 61:381–387. https://doi.org/10.1038/jhg.2016.1

    Article  PubMed  Google Scholar 

  • Garcia-Sanz P, Trivino JC, Mota A, Perez Lopez M, Colas E, Rojo-Sebastian A, Garcia A, Gatius S, Ruiz M, Prat J, Lopez-Lopez R, Abal M, Gil-Moreno A, Reventos J, Matias-Guiu X, Moreno-Bueno G (2017) Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma. Int J Cancer 140:1551–1563. https://doi.org/10.1002/ijc.30573

    Article  CAS  PubMed  Google Scholar 

  • Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526:68–74. https://doi.org/10.1038/nature15393

    Article  Google Scholar 

  • Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landen M, Moran JL, Purcell SM, Sklar P, Sullivan PF, Hultman CM, McCarroll SA (2016) Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci 19:1433–1441. https://doi.org/10.1038/nn.4402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–347. https://doi.org/10.1038/nature13394

    Article  CAS  PubMed  Google Scholar 

  • Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL (2014) De novo mutations in moderate or severe intellectual disability. PLoS Genet 10:e1004772. https://doi.org/10.1371/journal.pgen.1004772

    Article  PubMed  PubMed Central  Google Scholar 

  • Houge G, Rasmussen IH, Hovland R (2012) Loss-of-function CNKSR2 mutation is a likely cause of non-syndromic X-linked intellectual disability. Mol Syndromol 2:60–63. https://doi.org/10.1159/000335159

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Imai K, Ikeda H, Matsuda K, Takahashi Y, Inoue Y (2017) Ictal single photon emission computed tomography of myoclonic absence seizures. Brain Dev. https://doi.org/10.1016/j.braindev.2017.07.013

    Google Scholar 

  • Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–299. https://doi.org/10.1016/j.neuron.2012.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–221. https://doi.org/10.1038/nature13908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, Bernstein JA, Bejerano G (2016) M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet 48:1581–1586. https://doi.org/10.1038/ng.3703

    Article  CAS  PubMed  Google Scholar 

  • Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA (2012) De novo mutations in MLL cause Wiedemann–Steiner syndrome. Am J Hum Genet 91:358–364. https://doi.org/10.1016/j.ajhg.2012.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. https://doi.org/10.1038/ng.2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, Wissink-Lindhout W, Fenckova M, van den Akker WM, Kasri NN, Nillesen WM, Prescott T, Clark RD, Devriendt K, van Reeuwijk J, de Brouwer AP, Gilissen C, Zhou H, Brunner HG, Veltman JA, Schenck A, van Bokhoven H (2012) Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet 91:73–82. https://doi.org/10.1016/j.ajhg.2012.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koemans TS, Kleefstra T, Chubak MC, Stone MH, Reijnders MRF, de Munnik S, Willemsen MH, Fenckova M, Stumpel C, Bok LA, Sifuentes Saenz M, Byerly KA, Baughn LB, Stegmann APA, Pfundt R, Zhou H, van Bokhoven H, Schenck A, Kramer JM (2017) Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. PLoS Genet 13:e1006864. https://doi.org/10.1371/journal.pgen.1006864

    Article  PubMed  PubMed Central  Google Scholar 

  • Labonne JD, Lee KH, Iwase S, Kong IK, Diamond MP, Layman LC, Kim CH, Kim HG (2016) An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability. Hum Genet 135:757–771. https://doi.org/10.1007/s00439-016-1668-4

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Tate CM, You JS, Skalnik DG (2007) Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J Biol Chem 282:13419–13428. https://doi.org/10.1074/jbc.M609809200

    Article  CAS  PubMed  Google Scholar 

  • Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Lohner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C (2016) Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci 19:1194–1196. https://doi.org/10.1038/nn.4352

    Article  CAS  PubMed  Google Scholar 

  • Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D, Consortium UK, Deciphering Developmental Disorders S, Consortium NBRD, Pittman A, Carr LJ, Perez-Duenas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA (2017) Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 49:223–237. https://doi.org/10.1038/ng.3740

    Article  CAS  PubMed  Google Scholar 

  • Miyatake S, Koshimizu E, Fujita A, Fukai R, Imagawa E, Ohba C, Kuki I, Nukui M, Araki A, Makita Y, Ogata T, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N (2015) Detecting copy-number variations in whole-exome sequencing data using the eXome hidden Markov model: an ‘exome-first’ approach. J Hum Genet 60:175–182. https://doi.org/10.1038/jhg.2014.124

    Article  CAS  PubMed  Google Scholar 

  • Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, Yamaguchi-Kabata Y, Yokozawa J, Danjoh I, Saito S, Sato Y, Mimori T, Tsuda K, Saito R, Pan X, Nishikawa S, Ito S, Kuroki Y, Tanabe O, Fuse N, Kuriyama S, Kiyomoto H, Hozawa A, Minegishi N, Douglas Engel J, Kinoshita K, Kure S, Yaegashi N, To MJRPP, Yamamoto M (2015) Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 6:8018. https://doi.org/10.1038/ncomms9018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42:790–793. https://doi.org/10.1038/ng.646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–250. https://doi.org/10.1038/nature10989

    Article  PubMed  PubMed Central  Google Scholar 

  • Palumbo O, Palumbo P, Delvecchio M, Palladino T, Stallone R, Crisetti M, Zelante L, Carella M (2015) Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms. Am J Med Genet A 167A:438–444. https://doi.org/10.1002/ajmg.a.36872

    Article  PubMed  Google Scholar 

  • Pfau R, Tzatsos A, Kampranis SC, Serebrennikova OB, Bear SE, Tsichlis PN (2008) Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process. Proc Natl Acad Sci USA 105:1907–1912. https://doi.org/10.1073/pnas.0711865105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiao Y, Tyson C, Hrynchak M, Lopez-Rangel E, Hildebrand J, Martell S, Fawcett C, Kasmara L, Calli K, Harvard C, Liu X, Holden JJ, Lewis SM, Rajcan-Separovic E (2013) Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Clin Genet 83:145–154. https://doi.org/10.1111/j.1399-0004.2012.01860.x

    Article  CAS  PubMed  Google Scholar 

  • Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Ropke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schrock E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–1682. https://doi.org/10.1016/S0140-6736(12)61480-9

    Article  CAS  PubMed  Google Scholar 

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) 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 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  • Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 45:445–449. https://doi.org/10.1038/ng.2562 (449e1)

    Article  CAS  PubMed  Google Scholar 

  • Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241. https://doi.org/10.1038/nature10945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shilatifard A (2012) The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81:65–95. https://doi.org/10.1146/annurev-biochem-051710-134100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J, Suvisaari J, Chheda H, Blackwood D, Breen G, Pietilainen O, Gerety SS, Ayub M, Blyth M, Cole T, Collier D, Coomber EL, Craddock N, Daly MJ, Danesh J, DiForti M, Foster A, Freimer NB, Geschwind D, Johnstone M, Joss S, Kirov G, Korkko J, Kuismin O, Holmans P, Hultman CM, Iyegbe C, Lonnqvist J, Mannikko M, McCarroll SA, McGuffin P, McIntosh AM, McQuillin A, Moilanen JS, Moore C, Murray RM, Newbury-Ecob R, Ouwehand W, Paunio T, Prigmore E, Rees E, Roberts D, Sambrook J, Sklar P, St Clair D, Veijola J, Walters JT, Williams H, Swedish Schizophrenia S, Study I, Study DDD, Consortium UK, Sullivan PF, Hurles ME, O’Donovan MC, Palotie A, Owen MJ, Barrett JC (2016) Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci 19:571–577. https://doi.org/10.1038/nn.4267

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, Huang X, Fan J, Dong L, Chen G, Ma L, Yang J, Chen L, He M, Li M, Zhuang X, Huang K, Qiu K, Yin G, Guo G, Feng Q, Chen P, Wu Z, Wu J, Ma L, Zhao J, Luo L, Fu M, Xu B, Chen B, Li Y, Tong T, Wang M, Liu Z, Lin D, Zhang X, Yang H, Wang J, Zhan Q (2014) Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509:91–95. https://doi.org/10.1038/nature13176

    Article  CAS  PubMed  Google Scholar 

  • Strauss KA, Markx S, Georgi B, Paul SM, Jinks RN, Hoshi T, McDonald A, First MB, Liu W, Benkert AR, Heaps AD, Tian Y, Chakravarti A, Bucan M, Puffenberger EG (2014) A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder. Hum Mol Genet 23:6395–6406. https://doi.org/10.1093/hmg/ddu335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takata A, Xu B, Ionita-Laza I, Roos JL, Gogos JA, Karayiorgou M (2014) Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82:773–780. https://doi.org/10.1016/j.neuron.2014.04.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, Elliott A, Wylie H, Ardissone A, Rittinger O, Stewart F, Temple IK, Cole T, Childhood Overgrowth C, Mahamdallie S, Seal S, Ruark E, Rahman N (2017) Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am J Hum Genet 100:725–736. https://doi.org/10.1016/j.ajhg.2017.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaags AK, Bowdin S, Smith ML, Gilbert-Dussardier B, Brocke-Holmefjord KS, Sinopoli K, Gilles C, Haaland TB, Vincent-Delorme C, Lagrue E, Harbuz R, Walker S, Marshall CR, Houge G, Kalscheuer VM, Scherer SW, Minassian BA (2014) Absent CNKSR2 causes seizures and intellectual, attention, and language deficits. Ann Neurol 76:758–764. https://doi.org/10.1002/ana.24274

    Article  CAS  PubMed  Google Scholar 

  • Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T, Bevan AP, Bragin E, Chatzimichali EA, Gribble S, Jones P, Krishnappa N, Mason LE, Miller R, Morley KI, Parthiban V, Prigmore E, Rajan D, Sifrim A, Swaminathan GJ, Tivey AR, Middleton A, Parker M, Carter NP, Barrett JC, Hurles ME, FitzPatrick DR, Firth HV, Study DDD (2015) Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385:1305–1314. https://doi.org/10.1016/S0140-6736(14)61705-0

    Article  PubMed  PubMed Central  Google Scholar 

  • Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, Pilshofer V, Ceballos-Baumann A, Alhaddad B, Berutti R, Poewe W, Haack TB, Haslinger B, Strom TM, Winkelmann J (2016) Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet 99:1377–1387. https://doi.org/10.1016/j.ajhg.2016.10.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the patient’s family for participating in this work. This study was supported by the Ministry of Health, Labour and Welfare of Japan, a Grant-in-Aid for Scientific Research (A) (17H01539), (B) (16H05160) and (C) (15K10367) from the Japan Society for the Promotion of Science, Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science, Initiative on Rare and Undiagnosed Diseases in Pediatrics from the Japan Agency for Medical Research and Development.

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Author notes

  1. Takuya Hiraide and Mitsuko Nakashima contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takuya Hiraide, Kaori Yamoto, Tokiko Fukuda & Tsutomu Ogata

  2. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Mitsuko Nakashima & Naomichi Matsumoto

  3. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Mitsuko Nakashima, Kazushi Aoto & Hirotomo Saitsu

  4. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato

  5. Department of Pediatrics, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan

    Hiroko Ikeda

  6. Aoi-cho Children’s Clinic, Hamamatsu, Japan

    Yoko Sugie

  7. Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan

    Tadashi Kaname

  8. Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

    Kazuhiko Nakabayashi

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Correspondence to Naomichi Matsumoto or Hirotomo Saitsu.

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Hiraide, T., Nakashima, M., Yamoto, K. et al. De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism. Hum Genet 137, 95–104 (2018). https://doi.org/10.1007/s00439-017-1863-y

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