No evidence for copy number and methylation variation in H19 and KCNQ10T1 imprinting control regions in children born small for gestational age.

Rinki Murphy,Jörg Tost,John Md Thompson,Edwin A Mitchell

doi:10.1186/1471-2350-15-67

Abstract

BackgroundThere is a substantial genetic component for birthweight variation, and although there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown. The two imprinting control regions (ICRs) located on chromosome 11p15.5, involved in the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and the growth restriction disorder Silver-Russell syndrome (SRS), are prime epigenetic candidates for regulating fetal growth. We investigated whether common variation in copy number in the BWS/SRS 11p15 region or altered methylation levels at IGF2/H19 ICR or KCNQ10T1 ICR was associated with SGA.MethodsWe used a methylation-specific multiplex-ligation-dependent probe amplification assay to analyse copy number variation in the 11p15 region and methylation of IGF2/H19 and KCNQ10T1 ICRs in blood samples from 153 children (including 80 SGA), as well as bisulfite pyrosequencing to measure methylation at IGF2 differentially methylated region (DMR)0 and H19 DMR.ResultsNo copy number variants were detected in the analyzed cohort. Children born SGA had 2.7% lower methylation at the IGF2 DMR0. No methylation differences were detected at the H19 or KCNQ10T1 DMRs.ConclusionsWe confirm that a small hypomethylation of the IGF2 DMR0 is detected in peripheral blood leucocytes of children born SGA at term. Copy number variation within the 11p15 BWS/SRS region is not an important cause of non-syndromic SGA at term.

Highlights

There is a substantial genetic component for birthweight variation, and there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown
* Correspondence: R.Murphy@auckland.ac.nz 1Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand Full list of author information is available at the end of the article and birth weight [6], and we have previously demonstrated that genetic variation in certain genes associated with obesity and or type 2 diabetes is more prevalent in those born SGA than those born appropriate for gestational age (AGA) [7]
There was no significant difference in the methylation levels within the H19 differentially methylated region (DMR) or KCNQ10T1 DMR between children born SGA compared to non-SGA using multiplex ligation dependent probe amplification (MLPA) (Table 1)

Summary

Introduction

There is a substantial genetic component for birthweight variation, and there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown. The IGF2/H19 and KCNQ10T1 imprinting control regions (ICRs) are strong candidates for the epigenetic influence on birth weight variation as they are implicated in the neonatal overgrowth and growth restriction conditions of Beckwith Wiedemann (BWS) and Silver-Russell (SRS) syndromes, respectively. Copy number variation through uniparental disomy and small deletions or duplications affecting both these regulatory sites are recognised causes of BWS and SRS [12] Maternal duplication of this region is associated with growth retardation [13,14], while paternal duplication is associated with overgrowth at birth [8]

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