2. Academic Validation
  3. A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies

A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies

  • Am J Hum Genet. 2019 Apr 4;104(4):596-610. doi: 10.1016/j.ajhg.2019.02.001.
Kevin C J Nixon 1,  Justine Rousseau 2,  Max H Stone 3,  Mohammed Sarikahya 4,  Sophie Ehresmann 2,  Seiji Mizuno 5,  Naomichi Matsumoto 6,  Noriko Miyake 6,  DDD Study,  Diana Baralle 7,  Shane McKee 8,  Kosuke Izumi 9,  Alyssa L Ritter 9,  Solveig Heide 10,  Delphine Héron 10,  Christel Depienne 11,  Hannah Titheradge 12,  Jamie M Kramer 13,  Philippe M Campeau 14
Affiliations

Affiliations

  • 1 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
  • 2 Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.
  • 3 Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada; Division of Genetics and Development, Children's Health Research Institute, London, ON N6C 2V5, Canada.
  • 4 Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada.
  • 5 Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai 480-0392, Japan.
  • 6 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 7 Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
  • 8 Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, UK.
  • 9 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 10 APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau, Paris, France.
  • 11 Institut National de la Santé et de la Recherche Médicale (INSERM), U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 7104, INSERM U964, Université de Strasbourg, 67400 Illkirch, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg, Essen, 45147 Essen, Germany.
  • 12 Birmingham Women's and Children's National Health Service Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
  • 13 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada; Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada; Division of Genetics and Development, Children's Health Research Institute, London, ON N6C 2V5, Canada. Electronic address: [email protected].
  • 14 Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H4A 3J1, Canada. Electronic address: [email protected].
PMID: 30879640 DOI: 10.1016/j.ajhg.2019.02.001
Abstract

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.

Keywords

BAFopathies; Drosophila mushroom body; SMARCD1; SWI/SNF; intellectual disability; long-term memory; neurodevelopmental disorder.

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