Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes

Louise E. Docherty, F.I. Rezwan, Rebecca L. Poole, Hannah Jagoe, Hannah Lake, Gabrielle A. Lockett, Hasan Arshad, David I. Wilson, J.W. Holloway, I. Karen Temple, Deborah J. G. Mackay

Research output: Contribution to journalArticlepeer-review

68 Citations (SciVal)


Background: Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.

Design: We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith-Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.

Results: We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver-Russell syndrome presentations and one with pseudohypoparathyroidism 1B.

Conclusions: This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.
Original languageEnglish
Pages (from-to)229-238
Number of pages10
JournalJournal of Medical Genetics
Issue number4
Publication statusPublished - 05 Apr 2014


  • Alleles
  • Beckwith-Wiedemann Syndrome/genetics
  • CpG Islands/genetics
  • DNA Methylation/genetics
  • Diabetes Mellitus/genetics
  • Gene Expression Regulation
  • Genetic Association Studies
  • Genetic Loci/genetics
  • Genome, Human/genetics
  • Genomic Imprinting/genetics
  • Humans
  • Infant, Newborn
  • Infant, Newborn, Diseases/genetics
  • Oligonucleotide Array Sequence Analysis
  • Reproducibility of Results
  • Ribonucleoproteins, Small Nuclear/genetics


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