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 Nov 07
ISSN1537-6605
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