Background: Autism is a clinical syndrome with a complex interplay of etiologies. One major causative hypothesis specifies that alterations in long-range cortical connectivity underlie the pleiotropic manifestations of autism. Agenesis of the corpus callosum (AgCC) is the most common CNS malformation after spina bifida, with a birth incidence in excess of 1:4,000. Many AgCC individuals have a clinical diagnosis of autism or have social cognition deficits on the autism spectrum. Also like in autism, AgCC patients can have alterations in other major ipsilateral white matter tracts, including the cingulum bundle. Like autism, the genetics of AgCC is likely to be complex and prior case reports have suggested that de novo copy number variants (CNV’s) may play an important causative role.
Objectives: We hypothesized that the altered connectivity of AgCC overlaps with that of autism. We also hypothesized that AgCC patients would have a significant number of large candidate CNV’s and that these CNV’s may overlap with those identified in autism.
Methods: We identified patients with AgCC by a comprehensive radiological and clinical review. All participants or their legal guardian gave informed consent through an IRB approved human research protocol. Patients with complete or partial AgCC were included. Patients with globally diminished white matter volume or where other etiologies may secondarily result in AgCC were excluded (PMID: 17056927). Blood samples were obtained from the proband and both biological parents, when available. DNA was extracted and run on a Illumina 610 Quad Chip array. Data were analyzed using PennCNV. CNV’s that were selected for analysis contained greater than 9 SNPs, were longer than 30 kb, had a PennCNV confidence level above 10 and contained one or more genes. Manual curation and merging of contiguous large CNVs were conducted.
Results: 271 patient samples were run and high quality data were obtained from 96%. These data were compared against 1953 ethnically matched controls that were separately collected but run and analyzed on the same platform. We compared both CNVs binned by size and grouped by associated genes. Rare deletion CNV’s larger than 500 kb were significantly associated with AgCC patients as compared to controls (OR = 3.14; p = 0.0005). A complex deletion-duplication on chromosome 8p was recurrent in the AgCC cohort and at other loci, both the deletion and reciprocal duplication were found both with AgCC. We also analyzed the enrichment of genes within CNVs previously associated with autism and schizophrenia and found that CNV duplications in AgCC patients were significantly correlated with CNVs in these related neurodevelopmental patient cohorts (p = 0.004).
Conclusions: AgCC is a relatively common malformation of brain development often associated with ASD. Large CNV’s are highly correlated with AgCC patients and there is a specific enrichment of autism genes with AgCC CNV’s. These data support a strong etiologic link between autism and AgCC and suggest that further research is necessary to explore shared molecular and developmental pathways.
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See more of: Biological Mechanisms