title: Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity.
abstract: Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Family Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parente
authors.affiliation: St. Louis Children's Hospital, St. Louis, Missouri.
authors.forename: Caryn
authors.initials: C
authors.lastname: Garriga
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Ganka
authors.initials: G
authors.lastname: Douglas
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Psychology, St. Louis Children's Hospital, St. Louis, Missouri.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Araujo
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
mesh_terms: D000293:Adolescent; D000483:Alleles; D001007:Anxiety / Q000175:diagnosis / Q000235:genetics*; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D018389:Codon, Nonsense; D059472:Exome; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006963:Hyperphagia / Q000175:diagnosis / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D009765:Obesity / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome
chemical_list: D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D018389:Codon, Nonsense; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; C497683:FMR1 protein, human; C098003:neuroligin 2
keywords: NLGN2; anxiety; autism; obesity; synaptic function