title: Contactin 4 as an autism susceptibility locus.
abstract: Structural and sequence variation have been described in several members of the contactin (CNTN) and contactin-associated protein (CNTNAP) gene families in association with neurodevelopmental disorders, including autism. Using array comparative genome hybridization (CGH), we identified a maternally inherited ∼535 kb deletion at 3p26.3 encompassing the 5' end of the contactin 4 gene (CNTN4) in a patient with autism. Based on this finding and previous reports implicating genomic rearrangements of CNTN4 in autism spectrum disorders (ASDs) and 3p- microdeletion syndrome, we undertook sequencing of the coding regions of the gene in a local ASD cohort in comparison with a set of controls. Unique missense variants were identified in 4 of 75 unrelated individuals with ASD, as well as in 1 of 107 controls. All of the amino acid substitutions were nonsynonomous, occurred at evolutionarily conserved positions, and were, thus, felt likely to be deleterious. However, these data did not reach statistical significance, nor did the variants segregate with disease within all of the ASD families. Finally, there was no detectable difference in binding of two of the variants to the interacting protein PTPRG in vitro. Thus, additional larger studies will be necessary to determine whether CNTN4 functions as an autism susceptibility locus in combination with other genetic and/or environmental factors.
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Cottrell
authors.forename: Natalie
authors.initials: N
authors.lastname: Bir
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Varga
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Alvarez
authors.forename: Samuel
authors.initials: S
authors.lastname: Bouyain
authors.forename: Randall
authors.initials: R
authors.lastname: Zernzach
authors.forename: Devon L
authors.initials: DL
authors.lastname: Thrush
authors.forename: Johnna
authors.initials: J
authors.lastname: Evans
authors.forename: Michael
authors.initials: M
authors.lastname: Trimarchi
authors.forename: Eric M
authors.initials: EM
authors.lastname: Butter
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Gail E
authors.initials: GE
authors.lastname: Herman
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D015331:Cohort Studies; D058966:Contactins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005817:Genetic Counseling; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA
chemical_list: C098304:CNTN4 protein, human; D058966:Contactins