title: Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism.
abstract: Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Wang
authors.forename: Prescilla
authors.initials: P
authors.lastname: Carrion
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiao
authors.forename: Christine
authors.initials: C
authors.lastname: Tyson
authors.forename: Monica
authors.initials: M
authors.lastname: Hrynchak
authors.forename: Kristina
authors.initials: K
authors.lastname: Calli
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez-Rangel
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duban-Bedu
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.forename: Evica
authors.initials: E
authors.lastname: Rajcan-Separovic
authors.forename: M E
authors.initials: ME
authors.lastname: Suzanne Lewis
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D014314:Trisomy
keywords: Autism spectrum disorder (ASD); Chromosomal microarray analysis (CMA); Copy number variants (CNVs); Epilepsy; Intellectual disability (ID)