Purpose and Significance of the Study: The search for neurogenetic mechanisms and well-defined neurobiological features underlying autism and autism spectrum disorders has a clear public health impetus, as well as the potential to inform our understanding of how genetic variants work through the brain to confer susceptibility to serious neuropsychiatric disorders. Studying persons with copy number variations (CNVs) of the ~1.6 megabase 7q11.23 chromosomal region – which is hemizygously deleted (one copy of ~25 affected genes) in the rare disorder Williams Syndrome (MIM 194050) associated with hypersociability, and duplicated (three copies of the same ~25 affected genes) in the even rarer and more recently delineated 7q11.23 Duplication Syndrome (MIM 609757) is associated with autism – offers an unprecedented opportunity to discover fundamental information about the neurogenetic mechanisms of social behavior, cognitive disability, and brain plasticity during development and, in the 7q11.23 Duplication Syndrome, which is the subject of this proposal, to establish direct links with genes and pathways that play a role in autism.
The ~1.6 megabase 7q11.23 region that is hemideleted in Williams Syndrome and duplicated in the 7q11.23 Duplication Syndrome is quite stereotyped, with similar break points occurring in >95% of the Williams Syndrome population . Copy number variants (CNVs) in this particularly mutable genomic region are caused by unequal homologous recombination at flanking chromosome-specific low copy repeats with high sequence homology. These regions appear to be of recent origin (approximately 12-16 million years ago) and have evolved rapidly in the hominid lineage, leading to the speculation that they may have played a significant role in karyotypic evolution accompanying primate speciation . Inversion of this same segment has been found as a clinically silent variant in ~7% of the general population and in 27-35% of transmitting parents .
The 7q11.23 hemideletion of Williams Syndrome confers a unique clinical profile of striking behavioral features, such as hypersociability, combined with differential impact on cognitive functions – strength in language coupled with severe visuospatial impairment – and has received considerable attention as a well-defined genetic syndrome with a constellation of features that stand in opposition to those that characterize autism. The first case of duplication of the 7q11.23 Williams Syndrome region was identified in 2005, and a number of such individuals have now been reported. Interestingly, the phenotype of these patients diametrically contrasts with the Williams Syndrome clinical phenotype: whereas the cognitive phenotype in Williams Syndrome includes relative strength in language and severe problems in visuospatial construction, the 7q11.23 Duplication syndrome is characterized by just the opposite - severe speech and expressive language problems in the context of relative strength in visuospatial construction skills, as often seen in autism; moreover, individuals with the Duplication syndrome not only fail to manifest the characteristic Williams Syndrome hypersociability, they, in contrast, typically present with social problems, particularly autism. These contrasting clinical/cognitive phenotypes provide fascinating information about the behavioral effects of gene dosage (one gene copy vs. three) and an opportunity to link this information to neurogenetic mechanisms, but the brain phenotype of persons with the 7q11.23 Duplication Syndrome has not been delineated. This proposal would take advantage of the exceptional opportunity offered by the spectrum of genomic rearrangements at 7q11.23 with the goal of elucidating how genetic variation works through the brain to affect complex behaviors and cognition that are disrupted in autism.
Research Plan and Hypotheses: We will study 12 new child patients with the 7q11.23 Duplication Syndrome as well as unaffected siblings. With non-invasive multimodal magnetic resonance imaging (MRI)— structural MRI, functional MRI, diffusion tensor imaging (DTI), and myelin mapping—we will target those neural systems that in autism have been found to be specifically aberrant (e.g., brain regions involved in social cognition and language) or relatively spared (e.g., visuospatial construction). We will use the same published experimental methods [4-9] that have provided incisive information in Williams Syndrome, thus enabling key comparisons across 7q11.23 copy number variants (i.e., the duplication with three copies of each gene vs. the Williams Syndrome hemideletion with one copy), as compared to unaffected siblings and other matched typically developing controls. We hypothesize that copy number variation in the 7q11.23 region will be related to the brain phenotype of this well-defined genetic model of autism, and that some of the components of the brain phenotype will be gene-dose sensitive.