2. Academic Validation
  3. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

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

  • Mol Psychiatry. 2021 Jun;26(6):2013-2024. doi: 10.1038/s41380-020-0725-5.
Joost Kummeling # 1,  Diante E Stremmelaar # 1,  Nicholas Raun # 2 3,  Margot R F Reijnders 4,  Marjolein H Willemsen 1,  Martina Ruiterkamp-Versteeg 1,  Marga Schepens 1,  Calvin C O Man 1,  Christian Gilissen 1,  Megan T Cho 5,  Kirsty McWalter 5,  Margje Sinnema 4,  James W Wheless 6 7,  Marleen E H Simon 8,  Casie A Genetti 9 10,  Alicia M Casey 11,  Paulien A Terhal 8,  Jasper J van der Smagt 8,  Koen L I van Gassen 8,  Pascal Joset 12,  Angela Bahr 12,  Katharina Steindl 12,  Anita Rauch 12,  Elmar Keller 13,  Annick Raas-Rothschild 14 15,  David A Koolen 1,  Pankaj B Agrawal 9 10 16,  Trevor L Hoffman 17,  Nina N Powell-Hamilton 18 19,  Isabelle Thiffault 20 21,  Kendra Engleman 22,  Dihong Zhou 22,  Olaf Bodamer 9,  Julia Hoefele 23,  Korbinian M Riedhammer 23 24,  Eva M C Schwaibold 25,  Velibor Tasic 26,  Dirk Schubert 27,  Deniz Top 28,  Rolph Pfundt 1,  Martin R Higgs # 29,  Jamie M Kramer # 2 3,  Tjitske Kleefstra # 30
Affiliations

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.
  • 2 Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
  • 3 Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada.
  • 4 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6229 ER, Maastricht, The Netherlands.
  • 5 GeneDx, Gaithersburg, MD, 20877, USA.
  • 6 Division of Pediatric Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 7 Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program, Le Bonheur Children's Hospital, Memphis, TN, USA.
  • 8 Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 9 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.
  • 10 The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 11 Division of Pulmonary and Respiratory Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 12 Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.
  • 13 Division of Neuropediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland.
  • 14 Institute of Rare Disease, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
  • 15 Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
  • 16 Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 17 Regional Department of Genetics, Southern California Kaiser Permanente Medical Group, 1188N. Euclid Street, Anaheim, CA, 92801, USA.
  • 18 Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
  • 19 Department of Pathology and Laboratory Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
  • 20 Center for Pediatric Genomic Medicine, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
  • 21 Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
  • 22 Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
  • 23 Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 24 Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 25 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  • 26 Medical School Skopje, University Children's Hospital, Skopje, North Macedonia.
  • 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.
  • 28 Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
  • 29 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
  • 30 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 32346159 DOI: 10.1038/s41380-020-0725-5
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.

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