De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

  • Am J Hum Genet. 2020 Aug 6;107(2):311-324. doi: 10.1016/j.ajhg.2020.06.016.
Andreea Manole  1 ,  Stephanie Efthymiou  1 ,  Emer O'Connor  1 ,  Marisa I Mendes  2 ,  Matthew Jennings  3 ,  Reza Maroofian  1 ,  Indran Davagnanam  4 ,  Kshitij Mankad  5 ,  Maria Rodriguez Lopez  6 ,  Vincenzo Salpietro  1 ,  Ricardo Harripaul  7 ,  Lauren Badalato  8 ,  Jagdeep Walia  8 ,  Christopher S Francklyn  9 ,  Alkyoni Athanasiou-Fragkouli  1 ,  Roisin Sullivan  1 ,  Sonal Desai  10 ,  Kristin Baranano  10 ,  Faisal Zafar  11 ,  Nuzhat Rana  11 ,  Muhammed Ilyas  12 ,  Alejandro Horga  1 ,  Majdi Kara  13 ,  Francesca Mattioli  14 ,  Alice Goldenberg  15 ,  Helen Griffin  3 ,  Amelie Piton  14 ,  Lindsay B Henderson  16 ,  Benyekhlef Kara  17 ,  Ayca Dilruba Aslanger  17 ,  Joost Raaphorst  18 ,  Rolph Pfundt  19 ,  Ruben Portier  20 ,  Marwan Shinawi  21 ,  Amelia Kirby  22 ,  Katherine M Christensen  22 ,  Lu Wang  23 ,  Rasim O Rosti  23 ,  Sohail A Paracha  24 ,  Muhammad T Sarwar  24 ,  Dagan Jenkins  25 ,  SYNAPS Study Group  26 ,  Jawad Ahmed  24 ,  Federico A Santoni  27 ,  Emmanuelle Ranza  28 ,  Justyna Iwaszkiewicz  29 ,  Cheryl Cytrynbaum  30 ,  Rosanna Weksberg  30 ,  Ingrid M Wentzensen  16 ,  Maria J Guillen Sacoto  16 ,  Yue Si  16 ,  Aida Telegrafi  16 ,  Marisa V Andrews  21 ,  Dustin Baldridge  21 ,  Heinz Gabriel  31 ,  Julia Mohr  31 ,  Barbara Oehl-Jaschkowitz  32 ,  Sylvain Debard  33 ,  Bruno Senger  33 ,  Frédéric Fischer  33 ,  Conny van Ravenwaaij  34 ,  Annemarie J M Fock  34 ,  Servi J C Stevens  35 ,  Jürg Bähler  6 ,  Amina Nasar  8 ,  John F Mantovani  36 ,  Adnan Manzur  25 ,  Anna Sarkozy  25 ,  Desirée E C Smith  2 ,  Gajja S Salomons  2 ,  Zubair M Ahmed  37 ,  Shaikh Riazuddin  38 ,  Saima Riazuddin  37 ,  Muhammad A Usmani  37 ,  Annette Seibt  39 ,  Muhammad Ansar  40 ,  Stylianos E Antonarakis  41 ,  John B Vincent  7 ,  Muhammad Ayub  8 ,  Mona Grimmel  42 ,  Anne Marie Jelsig  43 ,  Tina Duelund Hjortshøj  43 ,  Helena Gásdal Karstensen  43 ,  Marybeth Hummel  44 ,  Tobias B Haack  45 ,  Yalda Jamshidi  46 ,  Felix Distelmaier  39 ,  Rita Horvath  3 ,  Joseph G Gleeson  23 ,  Hubert Becker  33 ,  Jean-Louis Mandel  14 ,  David A Koolen  19 ,  Henry Houlden  47
Affiliations
  • 1. Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • 2. Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
  • 3. Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
  • 4. Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • 5. Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
  • 6. Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
  • 7. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
  • 8. Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
  • 9. Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
  • 10. Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
  • 11. Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
  • 12. University of Islamabad, Islamabad, 45320, Pakistan.
  • 13. Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
  • 14. Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
  • 15. Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France.
  • 16. GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
  • 17. Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
  • 18. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.
  • 19. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
  • 20. Department of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands.
  • 21. Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 22. Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 23. Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
  • 24. Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
  • 25. Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
  • 26. SYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data.
  • 27. Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
  • 28. Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland.
  • 29. Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland.
  • 30. Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
  • 31. CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
  • 32. Biomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany.
  • 33. University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
  • 34. University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
  • 35. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands.
  • 36. Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 37. Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
  • 38. Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
  • 39. Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
  • 40. Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland.
  • 41. Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
  • 42. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
  • 43. Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
  • 44. Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA.
  • 45. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
  • 46. Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
  • 47. Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: [email protected].
PMID: 32738225 DOI: 10.1016/j.ajhg.2020.06.016
Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient Enzymes that charge Amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Keywords
aminoacyl-tRNA synthetase; developmental delay; epilepsy; neurodevelopment; neuropathy; next generation sequencing.