title: No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.
abstract: Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.
authors.affiliation: Yale University Department of Genetics, New Haven, Connecticut, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Murdoch
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America; Yale University Department of Pediatrics, New Haven, Connecticut, United States of America.
authors.forename: Abha R
authors.initials: AR
authors.lastname: Gupta
authors.affiliation: Yale University Department of Genetics, New Haven, Connecticut, United States of America; University of California, San Francisco, Department of Psychiatry, San Francisco, California, United States of America.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: University of California, San Francisco, Department of Psychiatry, San Francisco, California, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walker
authors.affiliation: Yale College, New Haven, Connecticut, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Keaney
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Fernandez
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Anyanwu
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Ober
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Raubeson
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: DiLullo
authors.affiliation: UCLA David Geffen School of Medicine, Los Angeles, California, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: Villa
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Zainabdul
authors.initials: Z
authors.lastname: Waqar
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sullivan
authors.affiliation: Yale University Child Study Center, New Haven, Connecticut, United States of America.
authors.forename: Luis
authors.initials: L
authors.lastname: Gonzalez
authors.affiliation: Yale University Department of Genetics, New Haven, Connecticut, United States of America; University of California, San Francisco, Department of Psychiatry, San Francisco, California, United States of America.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: UCLA School of Law, Los Angeles, California, United States of America.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Choe
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Yale University Department of Genetics, New Haven, Connecticut, United States of America; Yale University Child Study Center, New Haven, Connecticut, United States of America; University of California, San Francisco, Department of Psychiatry, San Francisco, California, United States of America.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense; D058966:Contactins / Q000235:genetics*; D056915:DNA Copy Number Variations; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C403049:CNTNAP2 protein, human; D018389:Codon, Nonsense; D058966:Contactins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins