Genome-Wide Allelic Methylation Analysis Reveals Disease-Specific Susceptibility to Multiple Methylation Defects in Imprinting Syndromes

ABSTRACT Genomic imprinting is the parent‐of‐origin‐specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith–Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver–Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader–Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN‐DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance. Genomic imprinting is the parent‐of‐origin specific allelic transcriptional silencing observed in mammals. Abnormal methylation at imprinted loci is associated with various imprinting syndromes. We analysed of 26 imprinted DMRs and identified multi‐locus hypomethyaltion in numerous BWS, TNDM and PHP‐1B patients, and an individual with SRS, but not in PWS or AS patients. A mutation screen of ZFP57, NLRP2, NLRP7 and KHDC3L revealed only one causative change, a ZFP57 1bp deletion, in a TNDM patient with multiple‐hypomethylation.