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Background  Silver-Russell syndrome (SRS) is a genetically and clinically heterogeneous disease. Although no protein coding gene defects have been reported in SRS patients, approximately 50% of SRS patients carry epimutations (hypomethylation) at the  IGF2/H19  imprinting control region 1 (ICR1). Proper methylation at ICR1 is crucial for the imprinted expression of  IGF2 , a fetal growth factor. CTCFL, a testis-specific protein, has recently been proposed to play a role in the establishment of DNA methylation at the murine equivalent of ICR1. A screen was undertaken to assess whether  CTCFL  is mutated in SRS patients with hypomethylation, to explore a link between the observed epimutations and a genetic cause of the disease.    Methodology/Principal Findings  DNA was obtained from 36 SRS patients with hypomethylation at ICR1. All  CTCFL  coding exons were sequenced and analyzed for duplications/deletions using both multiplex ligation-dependent probe amplification, with a custom  CTCFL  probe set, and genomic qPCR. Novel SNP alleles were analyzed for potential differential splicing  in vitro  utilizing a splicing assay. Neither mutations of  CTCFL  nor duplications/deletions were observed. Five novel SNPs were identified and have been submitted to dbSNP.  In silico  splice prediction suggested one novel SNP, IVS2-66A>C, activated a cryptic splice site, resulting in aberrant splicing and premature termination.  In vitro  splicing assays did not confirm predicted aberrant splicing.    Conclusions/Significance  As no mutations were detected at  CTCFL  in the patients examined, we conclude that genetic alterations of  CTCFL  are not responsible for the SRS hypomethylation. We suggest that analysis of other genes involved in the establishment of DNA methylation at imprinted genes, such as DNMT3A and DNMT3L, may provide insight into the genetic cause of hypomethylation in SRS patients.

No Evidence for Mutations of CTCFL/BORIS in Silver-Russell Syndrome Patients with IGF2/H19 Imprinting Control Region 1 Hypomethylation