2. Academic Validation
  3. Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder

Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder

  • Am J Hum Genet. 2019 Nov 7;105(5):1048-1056. doi: 10.1016/j.ajhg.2019.09.025.
Caroline M Dias 1,  Jaya Punetha 2,  Céline Zheng 3,  Neda Mazaheri 4,  Abolfazl Rad 5,  Stephanie Efthymiou 6,  Andrea Petersen 7,  Mohammadreza Dehghani 8,  Davut Pehlivan 9,  Jennifer N Partlow 10,  Jennifer E Posey 2,  Vincenzo Salpietro 6,  Alper Gezdirici 11,  Reza Azizi Malamiri 12,  Nihal M Al Menabawy 13,  Laila A Selim 13,  Mohammad Yahya Vahidi Mehrjardi 8,  Selina Banu 14,  Daniel L Polla 15,  Edward Yang 16,  Jamileh Rezazadeh Varaghchi 17,  Tadahiro Mitani 2,  Ellen van Beusekom 18,  Maryam Najafi 19,  Alireza Sedaghat 20,  Jennifer Keller-Ramey 21,  Leslie Durham 7,  Zeynep Coban-Akdemir 2,  Ender Karaca 22,  Valeria Orlova 3,  Lieke L M Schaeken 18,  Amir Sherafat 23,  Shalini N Jhangiani 24,  Valentina Stanley 25,  Gholamreza Shariati 26,  Hamid Galehdari 27,  Joseph G Gleeson 25,  Christopher A Walsh 10,  James R Lupski 28,  Elena Seiradake 3,  Henry Houlden 6,  Hans van Bokhoven 18,  Reza Maroofian 29
Affiliations

Affiliations

  • 1 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Developmental Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
  • 4 Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, 6135783151, Iran; Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, 6155689467, Iran.
  • 5 Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, 009851, Iran; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
  • 6 Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK.
  • 7 Randall Children's Hospital at Legacy Emanuel, Portland, OR 97227, USA.
  • 8 Medical Genetics Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
  • 11 Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, 34303, Turkey.
  • 12 Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6163764648, Iran.
  • 13 Pediatric Neurology and Metabolic Division, Cairo University Children Hospital, Egypt.
  • 14 Department of Pediatric Neurology, ICH and SSF Hospital Mirpur, Dhaka, 1216, Bangladesh.
  • 15 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands; CAPES Foundation, Ministry of Education of Brazil, 549 Brasília, Brazil.
  • 16 Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 17 Hasti Genetic Counseling Center of Welfare Organization of Southern Khorasan, Birjand, Iran.
  • 18 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
  • 19 Genome Research Division, Human Genetics Department, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
  • 20 Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
  • 21 GeneDx, Gaithersburg, MD 20877, USA.
  • 22 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 23 Department of Neurology, Faculty of Medicine, Bam University of Medical Sciences, Bam, Iran.
  • 24 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 25 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 26 Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, 6155689467, Iran; Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran.
  • 27 Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, 6135783151, Iran.
  • 28 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 29 Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK. Electronic address: r.maroofian@ucl.ac.uk.
PMID: 31668703 DOI: 10.1016/j.ajhg.2019.09.025
Abstract

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome Sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

Keywords

NTNG2; autism; developmental delay; intellectual disability; neurodevelopmental disorder.

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