title: Genome-wide methylation analysis in Silver-Russell syndrome patients.
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.
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: A R
authors.initials: AR
authors.lastname: Prickett
authors.affiliation: Fetal Growth and Development Group, Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Böhm
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Frost
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: W
authors.initials: W
authors.lastname: Puszyk
authors.affiliation: Fetal Growth and Development Group, Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Abu-Amero
authors.affiliation: Fetal Growth and Development Group, Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Stanier
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Fetal Growth and Development Group, Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, United Kingdom.
authors.forename: G E
authors.initials: GE
authors.lastname: Moore
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: R J
authors.initials: RJ
authors.lastname: Oakey
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D017422:Sequence Analysis, DNA; D056730:Silver-Russell Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: C492515:ANKRD11 protein, human; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D016160:Retinoblastoma Protein