Abstract
Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9013-z) contains supplementary material, which is available to authorized users.
Highlights
Autism (MIM 209850) is a neurodevelopmental disorder characterized by three core symptom domains: ritualisticrepetitive behaviors, impaired social interaction, and impaired communication and language [39]
De novo copy number changes appear to be enriched in sporadic autism, though some recurrent CNVs that are primarily de novo, such as 16p11.2 deletions and duplications, are occasionally inherited from an unaffected parent, suggesting incomplete penetrance for some autism-associated CNVs [3, 28, 50]
We hypothesized that children with autism who had additional phenotypic features or diagnoses suggestive of a developmental disturbance but who had normal cytogenetic testing would be more likely to harbor novel CNVs. We used this model for two reasons: 1) children with chromosomal abnormalities often have multiple or syndromic developmental anomalies and 2) we recently reported a pathogenic microdeletion in a child with autism and eye abnormalities, stimulating our interest in investigating other individuals with autism and additional developmental disturbances [5]
Summary
Autism (MIM 209850) is a neurodevelopmental disorder characterized by three core symptom domains: ritualisticrepetitive behaviors, impaired social interaction, and impaired communication and language [39]. The etiology of autism appears to be primarily genetic, with karyotypically detectable chromosomal abnormalities accounting for ~5– 7% of cases [22, 23, 36, 49]. Recent studies have suggested a significant role for CNVs, both de novo and inherited, in the etiology of autism [3, 28, 30, 44, 50]. De novo copy number changes appear to be enriched in sporadic (simplex) autism, though some recurrent CNVs that are primarily de novo, such as 16p11.2 deletions and duplications, are occasionally inherited from an unaffected parent, suggesting incomplete penetrance for some autism-associated CNVs [3, 28, 50]. Several of the recently highlighted mutations in autism, such as SHANK3 [7], NRXN1 [8, 19] and contactin 4 [38] have been identified in parents, some of whom exhibit features of a broader autism phenotype
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
