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

TitleHomozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder.
Publication TypeJournal Article
Year of Publication2019
AuthorsDias, CM, Punetha, J, Zheng, C, Mazaheri, N, Rad, A, Efthymiou, S, Petersen, A, Dehghani, M, Pehlivan, D, Partlow, JN, Posey, JE, Salpietro, V, Gezdirici, A, Malamiri, RAzizi, Menabawy, NMAl, Selim, LA, Mehrjardi, MYahya Vahi, Banu, S, Polla, DL, Yang, E, Varaghchi, JRezazadeh, Mitani, T, van Beusekom, E, Najafi, M, Sedaghat, A, Keller-Ramey, J, Durham, L, Coban-Akdemir, Z, Karaca, E, Orlova, V, Schaeken, LLM, Sherafat, A, Jhangiani, SN, Stanley, V, Shariati, G, Galehdari, H, Gleeson, JG, Walsh, CA, Lupski, JR, Seiradake, E, Houlden, H, van Bokhoven, H, Maroofian, R
JournalAm J Hum Genet
Volume105
Issue5
Pagination1048-1056
Date Published2019 11 07
ISSN1537-6605
KeywordsAdolescent, Adult, Child, Child, Preschool, Exome, Female, GPI-Linked Proteins, Homozygote, Humans, Intellectual Disability, Male, Mutation, Missense, Netrins, Neurodevelopmental Disorders, Pedigree, Whole Exome Sequencing, Young Adult
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.

DOI10.1016/j.ajhg.2019.09.025
Alternate JournalAm J Hum Genet
PubMed ID31668703
PubMed Central IDPMC6849109
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
G1001253 / MRC_ / Medical Research Council / United Kingdom
/ HHMI / Howard Hughes Medical Institute / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
WT104033AIA / WT_ / Wellcome Trust / United Kingdom
T32 NS043124 / NS / NINDS NIH HHS / United States
MR/J004758/1 / MRC_ / Medical Research Council / United Kingdom
T32 MH112510 / MH / NIMH NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
MR/S005021/1 / MRC_ / Medical Research Council / United Kingdom
MR/S01165X/1 / MRC_ / Medical Research Council / United Kingdom
MR/K000608/1 / MRC_ / Medical Research Council / United Kingdom
G0601943 / MRC_ / Medical Research Council / United Kingdom
S10 OD018521 / OD / NIH HHS / United States
R605/0717 / DMT_ / The Dunhill Medical Trust / United Kingdom
R01 NS048453 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
G108/638 / MRC_ / Medical Research Council / United Kingdom
R01 NS035129 / NS / NINDS NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
G0802760 / MRC_ / Medical Research Council / United Kingdom
202827/Z/16/Z / WT_ / Wellcome Trust / United Kingdom