Subgroup Analyses Suggest Interplay of Rare and Common Variants In the Etiology of Autism

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
10:00 AM
M. W. Marquardt, T. N. Takahashi and J. H. Miles, University of Missouri - Thompson Center for Autism and Neurodevelopmental Disorders, Columbia, MO

Autism may be caused by cytogenetic & genetic abnormalities including Fragile X, chromosomal aneuploidy and copy number variants (CNVs).  Children with these diagnoses often exhibit generalized dysmorphology &/or microcephaly (complex phenotype).  Children with no evidence of generalized dysmorphology or microcephaly and no recognized genetic or environmental syndrome are labeled essential or non-syndromic autism.  They are reported to have high genetic loading for autism based on family studies showing elevated histories of autism, psychiatric and behavioral disorders.  Higher SRS scores in sibs and parents suggests their autism is caused by additive common variants.


Test the hypothesis that some chromosomal, genetic, teratogenic and dysmorphic abnormalities that appear to cause autism may just lower the threshold for expression of the full autism phenotype.   


Children with classical autistic disorder were classified by identified causes; chromosomal (15 subjects) , clinically significant CNV (15) , genetic or environmental syndrome (9),  generalized dysmorphology of unknown cause (66). Remainder (221) were classified as essential autism. All were evaluated through an outpatient autism specialty clinic with medical, developmental and family histories, dysmorphology examinations, chromosomes, FISH &/or microarray, DNA for Fragile X. Diagnosis was by adherence to DSM-IV criteria for autistic disorder with 88% of diagnoses verified by ADOS &/or ADI-R. 


Children with complex autism, defined by dysmorphology, chromosomal aneuploidy or genetic syndromes  were clinically different than those with essential autism with higher seizure rates (31%  vs 14%, p=0.002), EEG abnormalities (33% vs 23%), and lower mean NVIQ (62 vs 81, p= 0.001). Sib recurrence was lower (5%) in the complex groups  compared to the essential group (15%).  However, family loading for autism, psychiatric and behavioral disorders did not differ significantly between essential & complex groups. All were significantly higher than in control families. Surprisingly the 15 children identified with CNVs more closely resembled essential autism (no seizures, nl EEGs, higher  NVIQs (81), high sex ratio (14:1) and high sib recurrence (13%).  But their family histories of autism & related disorders were similar to what is seen in both the essential or complex groups.


Finding that children with complex autism, essential autism and those with CNVs have comparable family histories of autism, psychiatric and behavioral histories suggests that the genetic disorders that we identify in children with autism are not wholly responsible for their autism phenotype.  If identified chromosomal and genetic syndromes were entirely responsible for causing the autism,  one would expect family loading to be no higher than in the general population.  Finding similar family histories across the groups implies that for most cytogenetic and genetic syndromes identified in children with autism, their causal effect is only partial and may just lower the threshold for the development of autism.  The surprising finding that the group with CNVs  clinically and genetically resembled those with essential autism suggests that common CNVs identified by current methodology may be more likely to identify autism specific genes than studies of children with complex phenotype autism.

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