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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.

SUBMITTER: Prickett AR

PROVIDER: S-EPMC4568568 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Genome-wide methylation analysis in Silver-Russell syndrome patients.

Prickett A R AR Ishida M M Böhm S S Frost J M JM Puszyk W W Abu-Amero S S Stanier P P Schulz R R Moore G E GE Oakey R J RJ

Human genetics 20150107 3

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 meas ...[more]

PMID: 25563730

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Project description:BACKGROUND:Imprinting 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). RESULTS:GWMA 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. CONCLUSIONS:GWMA 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.

Project description:Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the "IC1 hypomethylation" and "mUPD7" groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

Project description:BackgroundRecent 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 findingsWe 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/significanceThe 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.

Project description:BACKGROUND:Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. RESULTS:Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. CONCLUSIONS:We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.

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Genome-wide methylation analysis in Silver-Russell syndrome patients.

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Genome-wide methylation analysis in Silver-Russell syndrome patients.

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