Abstract
BackgroundImprinting disorders (IDs) show overlapping phenotypes, particularly in Silver–Russell syndrome (SRS), Temple syndrome (TS14), and Prader–Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA).ResultsGWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients.ConclusionsGWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.
Highlights
Imprinting disorders (IDs) show overlapping phenotypes, in Silver–Russell syndrome (SRS), Temple syndrome (TS14), and Prader–Willi syndrome (PWS)
The imprinting-associated differentially methylated regions (iDMRs) consist of germline DMRs imprinted during gametogenesis and secondary DMRs imprinted after fertilization, and the methylation pattern of the germline DMR hierarchically regulates that of the secondary DMR within the same imprinted region [1]
genome-wide methylation analysis (GWMA) GWMA was carried out using HumanMethylation450 BeadChip (HM450k) (Illumina, San Diego, CA) featuring approximately 475,000 CpGs across the human genome, except for CpGs which show age-related drift [23,24,25], sex-bias [26], and striking change before/after puberty [27]
Summary
Imprinting disorders (IDs) show overlapping phenotypes, in Silver–Russell syndrome (SRS), Temple syndrome (TS14), and Prader–Willi syndrome (PWS) These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. 27 out of 32 patients with TS14, who were diagnosed by molecular testing, were initially suspected as having SRS and/or PWS because of their clinical features, such as some NH-CSS features and muscular hypotonia, frequently observed in PWS patients in the neonatal period and early infancy [5] In this regard, Habib et al have performed transcriptome analysis using skin fibroblast and/or leukocyte samples obtained from patients with TS14 and SRS with H19LOM, showing decreased IGF2 expression in TS14 and SRS patients and decreased SNURF and IPW expression, which is the representative expression pattern of PWS, in TS14 patients [6]. Some genes including imprinted genes have very weak or no expression in leukocytes and skin fibroblasts, which are obtainable tissues from patients
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