Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Molecular Psychiatry volume 26, pages 2013–2024 (2021)Cite this article

Subjects

Abstract

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The genomic position and coding consequences of 14 different SETD1A variants.
Fig. 2: DNA fiber analysis to assess the impact of SETD1A variants.
Fig. 3: Clinical portrait photographs of patients with a SETD1A pathogenic variant.
Fig. 4: Mushroom body specific knockdown of Set1 causes defects in short- and long-term memory.

References

  1. Association AP diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

  2. Beckwith EJ, Geissmann Q, French AS, Gilestro GF. Regulation of sleep homeostasis by sexual arousal. eLife. 2017;6:e27445. pii.

    Article  PubMed  PubMed Central  Google Scholar 

  3. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee JH, Skalnik DG. Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A Histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Mol Cell Biol. 2008;28:609–18.

    Article  CAS  PubMed  Google Scholar 

  6. Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M, et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci USA. 2001;98:12902–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mohan M, Herz HM, Smith ER, Zhang Y, Jackson J, Washburn MP, et al. The COMPASS family of H3K4 methylases in Drosophila. Mol Cell Biol. 2011;31:4310–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takahashi YH, Westfield GH, Oleskie AN, Trievel RC, Shilatifard A, Skiniotis G. Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human. Proc Natl Acad Sci USA. 2011;108:20526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem. 2012;81:65–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li Y, Jiao J. Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via beta-catenin. J Cell Biol. 2017;216:1975–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tajima K, Yae T, Javaid S, Tam O, Comaills V, Morris R, et al. SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes. Nat Commun. 2015;6:8257.

    Article  CAS  PubMed  Google Scholar 

  12. Higgs MR, Sato K, Reynolds JJ, Begum S, Bayley R, Goula A, et al. Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Mol Cell. 2018;71:25–41.e26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eising E, Carrion-Castillo A, Vino A, Strand EA, Jakielski KJ, Scerri TS, et al. A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Mol Psychiatry. 2018;24:1065–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J, et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016;19:571–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yu X, Yang L, Li J, Li W, Li D, Wang R, et al. De novo and inherited SETD1A variants in early-onset Epilepsy. Neurosci Bull. 2019;35:1045–57.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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;36:928–30.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Neveling K, Feenstra I, Gilissen C, Hoefsloot LH, Kamsteeg EJ, Mensenkamp AR, et al. A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat. 2013;34:1721–6.

    Article  CAS  PubMed  Google Scholar 

  18. Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704.

    Article  CAS  PubMed  Google Scholar 

  19. Boonsawat P, Joset P, Steindl K, Oneda B, Gogoll L, Azzarello-Burri S, et al. Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genet Med. 2019;21:2043–58.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lessel D, Gehbauer C, Bramswig NC, Schluth-Bolard C, Venkataramanappa S, van Gassen KLI, et al. BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells. Brain. 2018;141:2299–311.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47:435–44.

    Article  CAS  PubMed  Google Scholar 

  22. Weiss K, Terhal PA, Cohen L, Bruccoleri M, Irving M, Martinez AF, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet. 2016;99:934–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Takata A, Xu B, Ionita-Laza I, Roos JL, Gogos JA, Karayiorgou M. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron. 2014;82:773–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guipponi MS, Santoni FA, Setola V, Gehrig C, Rotharmel M. Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS ONE. 2014;9:e112745.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jenett A, Rubin GM, Ngo TT, Shepherd D, Murphy C, Dionne H, et al. A GAL4-driver line resource for Drosophila neurobiology. Cell Rep. 2012;2:991–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jones SG, Nixon KCJ, Chubak MC, Kramer JM. Mushroom body specific transcriptome analysis reveals dynamic regulation of learning and memory genes after acquisition of long-term courtship memory in Drosophila. G3. 2018;8:3433–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Perkins LA, Holderbaum L, Tao R, Hu Y, Sopko R, McCall K, et al. The transgenic RNAi Project at Harvard Medical School: resources and validation. Genetics. 2015;201:843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Siegel RW, Hall JC. Conditioned responses in courtship behavior of normal and mutant Drosophila. Proc Natl Acad Sci USA. 1979;76:3430–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Koemans TS, Kleefstra T, Chubak MC, Stone MH, Reijnders MRF, de Munnik S, et al. Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. PLoS Genet. 2017;13:e1006864.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Koemans TS, Oppitz C, Donders RAT, van Bokhoven H, Schenck A, Keleman K, et al. Drosophila courtship conditioning as a measure of learning and memory. J Vis Exp. 2017;124.

  32. Shaw PJ, Cirelli C, Greenspan RJ, Tononi G. Correlates of sleep and waking in Drosophila melanogaster. Science. 2000;287:1834–7.

    Article  CAS  PubMed  Google Scholar 

  33. Huber R, Hill SL, Holladay C, Biesiadecki M, Tononi G, Cirelli C. Sleep homeostasis in Drosophila melanogaster. Sleep. 2004;27:628–39.

    Article  PubMed  Google Scholar 

  34. Gilestro GF, Cirelli C. pySolo: a complete suite for sleep analysis in Drosophila. Bioinformatics. 2009;25:1466–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bock I, Nemeth K, Pentelenyi K, Balicza P, Balazs A, Molnar MJ, et al. Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance. Gene. 2016;595:131–41.

    Article  CAS  PubMed  Google Scholar 

  36. Wiel L, Venselaar H, Veltman JA, Vriend G, Gilissen C. Aggregation of population-based genetic variation over protein domain homologues and its potential use in genetic diagnostics. Hum Mutat. 2017;38:1454–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–94.

    Article  CAS  PubMed  Google Scholar 

  38. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40:W452–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hiraide T, Nakashima M, Yamoto K, Fukuda T, Kato M, Ikeda H, et al. De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism. Hum Genet. 2018;137:95–104.

    Article  CAS  PubMed  Google Scholar 

  42. Blobel GA, Kadauke S, Wang E, Lau AW, Zuber J, Chou MM, et al. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol Cell. 2009;36:970–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Petruk S, Sedkov Y, Johnston DM, Hodgson JW, Black KL, Kovermann SK, et al. TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell. 2012;150:922–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hallson G, Hollebakken RE, Li T, Syrzycka M, Kim I, Cotsworth S, et al. dSet1 is the main H3K4 di- and tri-methyltransferase throughout Drosophila development. Genetics. 2012;190:91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brand AH, Manoukian AS, Perrimon N. Ectopic expression in Drosophila. Methods Cell Biol. 1994;44:635–54.

    Article  CAS  PubMed  Google Scholar 

  46. Chubak MC, Nixon KCJ, Stone MH, Raun N, Rice SL, Sarikahya M, et al. Individual components of the SWI/SNF chromatin remodelling complex have distinct roles in memory neurons of the Drosophila mushroom body. Dis Model Mech. 2019;12:dmm037325. pii.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Driver DI, Gogtay N, Rapoport JL. Childhood onset schizophrenia and early onset schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2013;22:539–55.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rajji TK, Ismail Z, Mulsant BH. Age at onset and cognition in schizophrenia: meta-analysis. Br J Psychiatry. 2009;195:286–93.

    Article  CAS  PubMed  Google Scholar 

  49. Kerimoglu C, Sakib MS, Jain G, Benito E, Burkhardt S, Capece V, et al. KMT2A and KMT2B mediate memory function by affecting distinct genomic regions. Cell Rep. 2017;20:538–48.

    Article  CAS  PubMed  Google Scholar 

  50. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Faundes V, Newman WG, Bernardini L, Canham N, Clayton-Smith J, Dallapiccola B, et al. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am J Hum Genet. 2018;102:175–87.

    Article  CAS  PubMed  Google Scholar 

  52. McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y, et al. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry. 2014;19:652–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Varga E, Nemes C, Tancos Z, Bock I, Berzsenyi S, Levay G, et al. Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance. Stem Cell Res. 2016;17:531–3.

    Article  CAS  PubMed  Google Scholar 

  55. Goriely A, McGrath JJ, Hultman CM, Wilkie AO, Malaspina D. “Selfish spermatogonial selection”: a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. Am J Psychiatry. 2013;170:599–608.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet. 2012;90:175–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim S, Kaang BK. Epigenetic regulation and chromatin remodeling in learning and memory. Exp Mol Med. 2017;49:e281.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Mukai J, Cannavo E, Crabtree GW, Sun Z, Diamantopoulou A, Thakur P et al. Recapitulation and reversal of schizophrenia-related phenotypes in setd1a-deficient mice. Neuron. 2019;104:1–17.

    Article  CAS  Google Scholar 

  59. Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, et al. Histone methylation regulates memory formation. J Neurosci. 2010;30:3589–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci. 2013;33:3452–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, et al. InterPro: the integrative protein signature database. Nucleic Acids Res. 2009;37:D211–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to all individuals and their parents for participating in this study. This work was supported by the Netherlands Organization for Health Research and Development (ZonMw grant 91718310) to TK, ERA-NET NEURON-102 SYNSCHIZ (grant 013-17-003 4538) to DS, Canadian Institutes of Health Research, Canadian Foundation for Innovation, and the Canada Research Chairs Program to JMK, MRC Career Development Fellowship (MR/P009085/1) and a University of Birmingham Fellowship to MRH. We thank the Bloomington Drosophila Stock Center at Indiana University for providing all Drosophila strains used in this study. Sequencing and analysis for patient 2 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141.

Author information

Author notes

  1. These authors contributed equally: Joost Kummeling, Diante E. Stremmelaar, Nicholas Raun, Martin R. Higgs, Jamie M. Kramer, Tjitske Kleefstra

Authors and Affiliations

  1. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Joost Kummeling, Diante E. Stremmelaar, Marjolein H. Willemsen, Martina Ruiterkamp-Versteeg, Marga Schepens, Calvin C. O. Man, Christian Gilissen, David A. Koolen, Rolph Pfundt & Tjitske Kleefstra

  2. Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada

    Nicholas Raun & Jamie M. Kramer

  3. Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada

    Nicholas Raun & Jamie M. Kramer

  4. Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6229 ER, Maastricht, The Netherlands

    Margot R. F. Reijnders & Margje Sinnema

  5. GeneDx, Gaithersburg, MD, 20877, USA

    Megan T. Cho & Kirsty McWalter

  6. Division of Pediatric Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

    James W. Wheless

  7. Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program, Le Bonheur Children’s Hospital, Memphis, TN, USA

    James W. Wheless

  8. Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Marleen E. H. Simon, Paulien A. Terhal, Jasper J. van der Smagt & Koen L. I. van Gassen

  9. Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital/Harvard Medical School, Boston, MA, USA

    Casie A. Genetti, Pankaj B. Agrawal & Olaf Bodamer

  10. The Manton Center for Orphan Disease Research, Boston Children’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Casie A. Genetti & Pankaj B. Agrawal

  11. Division of Pulmonary and Respiratory Diseases, Boston Children’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Alicia M. Casey

  12. Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland

    Pascal Joset, Angela Bahr, Katharina Steindl & Anita Rauch

  13. Division of Neuropediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland

    Elmar Keller

  14. Institute of Rare Disease, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel

    Annick Raas-Rothschild

  15. Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Annick Raas-Rothschild

  16. Division of Newborn Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Pankaj B. Agrawal

  17. Regional Department of Genetics, Southern California Kaiser Permanente Medical Group, 1188N. Euclid Street, Anaheim, CA, 92801, USA

    Trevor L. Hoffman

  18. Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA

    Nina N. Powell-Hamilton

  19. Department of Pathology and Laboratory Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Nina N. Powell-Hamilton

  20. Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Isabelle Thiffault

  21. Division of Clinical Genetics, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Isabelle Thiffault

  22. Department of Pediatrics, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Kendra Engleman & Dihong Zhou

  23. Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Julia Hoefele & Korbinian M. Riedhammer

  24. Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Korbinian M. Riedhammer

  25. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Eva M. C. Schwaibold

  26. Medical School Skopje, University Children’s Hospital, Skopje, North Macedonia

    Velibor Tasic

  27. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Dirk Schubert

  28. Department of Pediatrics, Dalhousie University, Halifax, NS, Canada

    Deniz Top

  29. Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK

    Martin R. Higgs

Authors
  1. Joost Kummeling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diante E. Stremmelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas Raun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margot R. F. Reijnders
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marjolein H. Willemsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martina Ruiterkamp-Versteeg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marga Schepens
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Calvin C. O. Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christian Gilissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Megan T. Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kirsty McWalter
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Margje Sinnema
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James W. Wheless
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Marleen E. H. Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Casie A. Genetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Alicia M. Casey
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Paulien A. Terhal
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jasper J. van der Smagt
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Koen L. I. van Gassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Pascal Joset
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Angela Bahr
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Katharina Steindl
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Anita Rauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Elmar Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Annick Raas-Rothschild
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. David A. Koolen
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Pankaj B. Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Trevor L. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Nina N. Powell-Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Isabelle Thiffault
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Kendra Engleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Dihong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Olaf Bodamer
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Julia Hoefele
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Korbinian M. Riedhammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Eva M. C. Schwaibold
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Velibor Tasic
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Dirk Schubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Deniz Top
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Rolph Pfundt
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Martin R. Higgs
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. Jamie M. Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  43. Tjitske Kleefstra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tjitske Kleefstra.

Ethics declarations

Conflict of interest

All contributors have read and approved the submission to the journal. MTC and KM are employees of GeneDx. We are not aware of any other conflict of interest.

Ethics

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study as part of the diagnostic workflow. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kummeling, J., Stremmelaar, D.E., Raun, N. et al. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome. Mol Psychiatry 26, 2013–2024 (2021). https://doi.org/10.1038/s41380-020-0725-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0725-5

This article is cited by

Search

Advanced search

Quick links