title: Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression.
abstract: Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem,Edmond J. Safra campus, Jerusalem 91904, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Ben-David
authors.forename: Einat
authors.initials: E
authors.lastname: Granot-Hershkovitz
authors.forename: Galya
authors.initials: G
authors.lastname: Monderer-Rothkoff
authors.forename: Elad
authors.initials: E
authors.lastname: Lerer
authors.forename: Shlomit
authors.initials: S
authors.lastname: Levi
authors.forename: Maya
authors.initials: M
authors.lastname: Yaari
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ebstein
authors.forename: Nurit
authors.initials: N
authors.lastname: Yirmiya
authors.forename: Sagiv
authors.initials: S
authors.lastname: Shifman
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide