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Thursday, May 15, 2008
Champagne Terrace/Bordeaux (Novotel London West)
11:30 AM
Background: Post-mortem and MRI studies have identified several neural structures that are anatomically abnormal in autism patients, including the cerebellum. Posterior cerebellar hypoplasia and a decrease in the number of Purkinje cells have consistently been reported in the autistic brain. These are neural developmental phenotypes, suggesting that genes regulating cerebellar development may confer autism susceptibility. Few human cerebellar developmental genes have been described. We recently characterized a new human cerebellar malformation (CbM) locus on chromosome 6p25 at the molecular level by deletion mapping. Furthermore, we are systematically searching for CbM genes, generating the only DNA and clinical databank for CbMs.
Objectives: To determine the overlap between CbM loci and autism loci throughout the genome.
Methods: We performed exhaustive literature and database searches to identify cytogenetic abnormalities, copy number variants, or linkage at all 20 CbM cytogenetic loci in patients with autism.
Results: Among patients with autism we identified 5 with cytogenetic abnormalities and 9 with copy number variants of 6p25. Suggestive linkage to 6p25 in autism has also been reported. CT or MRI scans were not readily available for most autism patients to evaluate for CbM. Notably, however, the CbM patient with the smallest 6p25 deletion has a sibling with the identical 6p25 deletion and a diagnosis of autism, firmly establishing a link between CbM and autism at this locus. We further identified all 20 CbM loci in patients with autism. 18/20 (90%) CbM loci have at least 2 independent lines of evidence that they are also autism loci.
Conclusions: Cerebellar developmental phenotypes have been consistently reported in patients with autism suggesting that genes involved in cerebellar development may also contribute to autism pathophysiology. We recommend screening 6p25 deletion patients for CbMs and evaluating for autism. Our data further suggest that CbM patients may characterize a subset of autism patients.
Objectives: To determine the overlap between CbM loci and autism loci throughout the genome.
Methods: We performed exhaustive literature and database searches to identify cytogenetic abnormalities, copy number variants, or linkage at all 20 CbM cytogenetic loci in patients with autism.
Results: Among patients with autism we identified 5 with cytogenetic abnormalities and 9 with copy number variants of 6p25. Suggestive linkage to 6p25 in autism has also been reported. CT or MRI scans were not readily available for most autism patients to evaluate for CbM. Notably, however, the CbM patient with the smallest 6p25 deletion has a sibling with the identical 6p25 deletion and a diagnosis of autism, firmly establishing a link between CbM and autism at this locus. We further identified all 20 CbM loci in patients with autism. 18/20 (90%) CbM loci have at least 2 independent lines of evidence that they are also autism loci.
Conclusions: Cerebellar developmental phenotypes have been consistently reported in patients with autism suggesting that genes involved in cerebellar development may also contribute to autism pathophysiology. We recommend screening 6p25 deletion patients for CbMs and evaluating for autism. Our data further suggest that CbM patients may characterize a subset of autism patients.