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Genome-wide methylation analysis in Silver–Russell syndrome patients

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Abstract

Silver–Russell syndrome (SRS) is a clinically heterogeneous disorder characterised by severe in utero growth restriction and poor postnatal growth, body asymmetry, irregular craniofacial features and several additional minor malformations. The aetiology of SRS is complex and current evidence strongly implicates imprinted genes. Approximately, half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain, and around 10 % have maternal uniparental disomy of chromosome 7. We measured DNA methylation in 18 SRS patients at >485,000 CpG sites using DNA methylation microarrays. Using a novel bioinformatics methodology specifically designed to identify subsets of patients with a shared epimutation, we analysed methylation changes genome-wide as well as at known imprinted regions to identify SRS-associated epimutations. Our analysis identifies epimutations at the previously characterised domains of H19/IGF2 and at imprinted regions on chromosome 7, providing proof of principle that our methodology can detect DNA methylation changes at imprinted loci. In addition, we discovered two novel epimutations associated with SRS and located at imprinted loci previously linked to relevant mouse and human phenotypes. We identify RB1 as an additional imprinted locus associated with SRS, with a region near the RB1 differentially methylated region hypermethylated in 13/18 (~70 %) patients. We also report 6/18 (~33 %) patients were hypermethylated at a CpG island near the ANKRD11 gene. We do not observe consistent co-occurrence of epimutations at multiple imprinted loci in single SRS individuals. SRS is clinically heterogeneous and the absence of multiple imprinted loci epimutations reflects the heterogeneity at the molecular level. Further stratification of SRS patients by molecular phenotypes might aid the identification of disease causes.

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Abbreviations

SRS:

Silver–Russell syndrome

ICR1:

Imprinting control region 1

MLMD:

Multi-locus methylation defect

DMR:

Differentially methylated region

FDR:

False discovery rate

RFLP:

Restriction fragment length polymorphism

piRNA:

Piwi-interacting RNA

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Acknowledgments

We thank Vardhman Rakyan for technical advice on genome-wide methylation analysis methodologies, and Seth Seegobin for his help with some statistical elements of the analysis. This work was funded by the Wellcome Trust grants 084358/Z/07/Z and 085448/Z/08/Z and the MRC grant reference number G1001689. The authors acknowledge support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Their support is through access to the Beadchip array scanner and other equipment in the genomics core facility and technical assistance from Muddassar Mirza and Efterpi Papouli.

Conflict of interest

The author(s) declare that they have no competing interests.

Authors’ contributions

A.R.P. generated the in-house Illumina® 450k human methylation microarray data, further developed and implemented the data analysis approach, performed most of the data analyses, wrote the manuscript and prepared Tables and Figures. M.I. performed replication analysis using bisulfite mutagenesis analyses of selected regions, collated SRS patient information, and prepared some of the Tables. S.B. prepared DNA sample libraries for analysis on the Illumina® 450 k human microarray. J.F. collated SRS patient information, and with W.P., extracted DNA from some of the control blood samples, and prepared MeDIP libraries. S.A–A. provided patient information and performed locus-specific test for DNA methylation at the H19 ICR1 in patient samples. P.S. provided intellectual contributions. R.S. conceived the data analysis approach, created the original R implementation, consulted on its further development, performed some data analyses, and wrote the manuscript. G.M. contributed to the conception and design of the experiments and provided SRS patient sample DNAs. R.J.O. contributed to the conception and design of the experiments and wrote the paper. All authors contributed to the final version of the paper.

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Author notes

  1. J. M. Frost

    Present address: Plant and Microbial Biology Department, University of California Berkeley, 231 Koshland Hall, Berkeley, CA, 94720, USA

  2. W. Puszyk

    Present address: Department of Pathology, Health Sciences Center, University of Florida, Gainesville, FL, USA

Authors and Affiliations

  1. Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, London, UK

    A. R. Prickett, S. Böhm, J. M. Frost, W. Puszyk, R. Schulz & R. J. Oakey

  2. Fetal Growth and Development Group, Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, UK

    M. Ishida, S. Abu-Amero, P. Stanier & G. E. Moore

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  1. A. R. Prickett
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Correspondence to R. Schulz, G. E. Moore or R. J. Oakey.

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A. R. Prickett, M. Ishida, R. Schulz, G. E. Moore and R. J. Oakey contributed equally.

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Description of additional data files: 1. Additional data CpG islands: lists CpG islands examined in the methylation analysis ranked in descending order of absolute CpG island score. 2. Additional data gene promoter regions: lists the promoters in the methylation analysis ranked in descending order of absolute promoter score. 3. Additional data gene body regions: lists gene bodies examined in the methylation analysis ranked in descending order of absolute body score

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Prickett, A.R., Ishida, M., Böhm, S. et al. Genome-wide methylation analysis in Silver–Russell syndrome patients. Hum Genet 134, 317–332 (2015). https://doi.org/10.1007/s00439-014-1526-1

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  • DOI: https://doi.org/10.1007/s00439-014-1526-1

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