Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression
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Abstract
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic
or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely,
chromosomal translocations or inversions of chromosome 11p15.5 are associated with
BWS but the molecular pathophysiology in such cases is not understood. In our series
of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints
map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications
adjacent to the breakpoints could disrupt genomic sequences important for imprinted
gene regulation. An alternate hypothesis was that epigenetic alterations of as yet
unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen
custom microarray was designed representing all non-repetitive sequences in the telomeric
33 Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5
translocations and inversions, we found no evidence of microdeletions/microduplications.
DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment
by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray
analysis revealed a gain of DNA methylation in the translocation/inversion patients
affecting the p-ter segment of chromosome 11p15, including both imprinted domains.
BWS patients that inherited a maternal translocation or inversion also demonstrated
reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In
summary, our data demonstrate that translocations and inversions involving imprinted
domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted
gene expression in cis, suggesting that these epigenetic alterations are generated
by an alteration in "chromatin context".