Recommendations for a nomenclature system for reporting methylation aberrations in imprinted domains

Abstract

The analysis of DNA methylation has become routine in the pipeline for diagnosis of imprinting disorders, with many publications reporting aberrant methylation associated with imprinted differentially methylated regions (DMRs). However, comparisons between these studies are routinely hampered by the lack of consistency in reporting sites of methylation evaluated. To avoid confusion surrounding nomenclature, special care is needed to communicate results accurately, especially between scientists and other health care professionals. Within the European Network for Human Congenital Imprinting Disorders we have discussed these issues and designed a nomenclature for naming imprinted DMRs as well as for reporting methylation values. We apply these recommendations for imprinted DMRs that are commonly assayed in clinical laboratories and show how they support standardized database submission. The recommendations are in line with existing recommendations, most importantly the Human Genome Variation Society nomenclature, and should facilitate accurate reporting and data exchange among laboratories and thereby help to avoid future confusion.

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

“…Gene expression is controlled by the methylation status of the two imprinting centres: H19 / IGF2 :IG DMR (also called ICR1 (Imprinting Control Region 1)) for the telomeric domain and KCNQ1OT1 :TSS DMR (also called ICR2) for the centromeric domain (figure 1). 6 In addition to the imprinting centres, enhancers located in both domains control the expression of the genes located in the region. Within the telomeric domain, common enhancers shared by IGF2 and H19 are located 5’ of H19 7.…”

“…ICR1 regulates the expression of the non-coding RNA H19 and the IGF2 gene. ICR1 is methylated only on the paternal allele and unmethylated on the maternal allele 6. On the maternal allele, the ubiquitous Zinc-finger DNA-binding protein CTCF can bind to the unmethylated ICR, acting as an insulator and blocking the interaction of downstream enhancers with the IGF2 promoter, leading to transcriptional silencing of IGF2 .…”

“…The absence of methylation at ICR2 on the paternal allele allows the expression of KCNQ1OT1 , which in turn silences all genes of the domain. On the maternal allele, the absence of expression of KCNQ1OT1 allows the expression of Cyclin Dependant Kinase Inhibitor 1C ( CDKN1C ), an inhibitor of cell proliferation and Potassium Channel Voltage Gated KQT-family number 1 ( KCNQ1 ) 6. ICR, Imprinting Control Region.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…155 ). GNAS shows differential methylation at four distinct DMRs: one paternally methylated-DMR (GNAS-NESP:TSS-DMR) and three maternally methylated-DMRs (GNAS-AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS-DMR, according to the current nomenclature 156 ). Loss of methylation at GNAS A/B:TSS-DMR is detected in all patients with PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] .…”

NLRPs, the subcortical maternal complex and genomic imprinting

“…However, the specific aspect that makes imprinted DMRs unique is not their germline status, but their ability to maintain parent-of-origin allelic methylation during pre-implantation reprogramming (Smallwood et al 2011, Smith et al 2014. To date, there are 38 known germline-derived imprinted DMRs in humans, the majority originating in the oocyte, that retain life-long allelic methylation in adult tissues (Monk et al 2016). It has been shown that imprinted DMRs are selectively protected from the demethylation that occurs in the zygote immediately after fertilization.…”