title: Disruption of neurexin 1 associated with autism spectrum disorder.
abstract: Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
authors.affiliation: Molecular Neurogenetics Unit, Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.forename: Shotaro
authors.initials: S
authors.lastname: Kishikawa
authors.forename: Anne W
authors.initials: AW
authors.lastname: Higgins
authors.forename: Ihn-Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Donovan
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Eric
authors.initials: E
authors.lastname: Lally
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
authors.forename: Juliane
authors.initials: J
authors.lastname: Najm
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.forename: Maria
authors.initials: M
authors.lastname: Descartes
authors.forename: Lynn
authors.initials: L
authors.lastname: Holt
authors.forename: Stephen
authors.initials: S
authors.lastname: Braddock
authors.forename: Robin
authors.initials: R
authors.lastname: Troxell
authors.forename: Lee
authors.initials: L
authors.lastname: Kaplan
authors.forename: Fred
authors.initials: F
authors.lastname: Volkmar
authors.forename: Ami
authors.initials: A
authors.lastname: Klin
authors.forename: Katherine
authors.initials: K
authors.lastname: Tsatsanis
authors.forename: David J
authors.initials: DJ
authors.lastname: Harris
authors.forename: Ilse
authors.initials: I
authors.lastname: Noens
authors.forename: David L
authors.initials: DL
authors.lastname: Pauls
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Quade
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002869:Chromosome Aberrations; D002889:Chromosomes, Human, Pair 2; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: D006023:Glycoproteins; D009479:Neuropeptides; C112162:neurexophilin