Rearrangements of 7q11.23: disorders of the epigenome

Rearrangements of a 1.5 Mb region on chromosome 7q11.23 produce two distinct multisystem developmental disorders. Deletion of this region causes Williams-Beuren syndrome (WS; MIM 194050) and the reciprocal duplication causes 7q11.23 duplication syndrome (Dup7; MIM 609757). Individuals with WS and Dup7 show an array of contrasting and overlapping phenotypes, including variable intellectual disability, Attention Deficit Hyperactivity Disorder, social disinhibition and anxiety. Rearrangements at 7q11.23 provide an excellent model for studying gene dosage sensitivity in neurodevelopment and the molecular mechanism of related neuropsychiatric disorders. Little is known about how rearrangements at 7q11.23 contribute to the manifestation of specific phenotypes in these disorders. Several genes at this locus have been associated with epigenetic mechanisms and parent-of-origin dependent expression of specific phenotypes have been noted. To understand the impact of rearrangements at 7q11.23 on the epigenome, I have studied parent-of-origin dependent expression of individual genes at this locus, as well as genome-wide DNA methylation. Here I provide the first evidence to show that rearrangements of 7q11.23 result in dose-dependent changes to DNA methylation in peripheral blood from children with WS and Dup7. Aberrant DNA methylation was also identified in cortical neurons from a mouse model of WS, suggesting that DNA methylation is likely disrupted in neural tissue from individuals with 7q11.23 rearrangements. Using a combination of rare atypical deletions and duplications of 7q11.23 and mice with hemizygous deletions of Gtf2i and Gtf2ird1, I provide the first evidence that the TFII-I family of transcription factors contribute to aberrant DNA methylation when deleted or duplicated. Lastly, I identified monoallelic expression of Fkbp6, a gene involved in meiosis and piRNA biogenesis, in mouse and human cortical tissue, which may contribute to parent-of-origin dependent expression of phenotypes in WS. These data suggest WS and Dup7 are disorders of the epigenome, and that DNA methylation may be an important mechanism in the pathogenesis of these disorders.Ph.D.2018-12-19 00:00:0