2. Academic Validation
  3. Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

  • Am J Hum Genet. 2020 Apr 2;106(4):467-483. doi: 10.1016/j.ajhg.2020.02.015.
Tiong Yang Tan 1,  Jiří Sedmík 2,  Mark P Fitzgerald 3,  Rivka Sukenik Halevy 4,  Liam P Keegan 2,  Ingo Helbig 3,  Lina Basel-Salmon 5,  Lior Cohen 6,  Rachel Straussberg 7,  Wendy K Chung 8,  Mayada Helal 8,  Reza Maroofian 9,  Henry Houlden 9,  Jane Juusola 10,  Simon Sadedin 11,  Lynn Pais 12,  Katherine B Howell 13,  Susan M White 14,  John Christodoulou 14,  Mary A O'Connell 15
Affiliations

Affiliations

  • 1 Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia. Electronic address: tiong.tan@vcgs.org.au.
  • 2 Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic.
  • 3 Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
  • 5 Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Felsenstein Medical Research Center, Petah Tikva 49100, Israel.
  • 6 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49100, Israel.
  • 7 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Pediatric Neurology Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49100, Israel.
  • 8 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
  • 9 Department of Neuromuscular Disorders, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
  • 10 GeneDx, Gaithersburg, MD 20877, USA.
  • 11 Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia.
  • 12 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 13 Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia; Department of Neurology, Royal Children's Hospital, Parkville 3052, Australia.
  • 14 Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia.
  • 15 Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address: mary.oconnell@ceitec.muni.cz.
PMID: 32220291 DOI: 10.1016/j.ajhg.2020.02.015
Abstract

The RNA editing Enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the Others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

Keywords

ADAR2; RNA editing; epilepsy; intellectual disability; microcephaly; migrating focal seizures.

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