Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome

PLoS One. 2013;8(3):e60105. doi: 10.1371/journal.pone.0060105. Epub 2013 Mar 22.


Background: Recent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters.

Methodology/principal findings: We identified H19-DMR epimutation in cases 1-43 (group 1), upd(7)mat in cases 44-52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53-138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ∼3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC.

Conclusions/significance: The results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People / genetics
  • DNA Methylation / genetics
  • Epigenesis, Genetic / genetics
  • Female
  • Humans
  • Male
  • Silver-Russell Syndrome / genetics*
  • Uniparental Disomy / genetics

Grants and funding

This work was funded by Grants-in-Aid for Scientific Research (A) (22249010) and Research (B) (21028026) from the Japan Society for the Promotion of Science (, by Grant for Research on Rare and Intractable Diseases (H24-042) from the Ministry of Health, Labor and Welfare (, and by Grant for National Center for Child Health and Development (23A-1) ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.