Beckwith–Wiedemann syndrome in sibs discordant for IC2 methylation

Niederhoffer, Karen Y.; Peñaherrera, Maria S.; Pugash, D.; Rupps, Rosemarie; Arbour, Laura; Tessier, Francine; Choufani, Sanaa; Zhao, Cheng; Manokhina, Irina; Shuman, Cheryl; Robinson, Wendy P.; Weksberg, Rosanna; Boerkoel, Cornelius F.

doi:10.1002/ajmg.a.35377

Cited by 6 publications

(6 citation statements)

References 26 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comparative analysis of the epigenome has recently been conducted in twins showing discordances in mental disease [13], [14], multiple sclerosis [15], or without any specific disease [16]. Some of these studies examined DNA methylation at specific imprinted loci [17]–[20], whereas, genome-wide DNA methylation was analyzed in others [14]–[16], [21]. In this report, we compared whole genome sequences and DNA methylation patterns in discordant RTT twins with a MECP2 mutation in order to determine the genetic or epigenetic factor(s) responsible for the inter-twin differences in clinical severity.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

et al. 2013

View full text Add to dashboard Cite

Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.

show abstract

Section: Introductionmentioning

confidence: 99%

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

et al. 2013

View full text Add to dashboard Cite

show abstract

“…However, there are reports on families with two BWS sibs, 43 , 50 with one sib showing a KCNQ1OT1 :TSS-DMR hypomethylation and the second one showing the same epimutation but as part of an MLID. Although this situation seems to be rare, it illustrates that MLID also has to be considered in BWS testing.…”

Section: Interpretation Of Diagnostic Testing Resultsmentioning

confidence: 99%

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

et al. 2016

Self Cite

View full text Add to dashboard Cite

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature.

show abstract

“…PLAGL1 regulates growth, and it can be considered to be a tumor-suppressor gene that regulates cell-cycle arrest and apoptosis [ 61 ]. Some reports have suggested that hypomethylation of PLAGL1 is related to BWS, which often exhibits organomegaly [ 62 , 63 ]. NNAT is another imprinted gene which was hypomethylated in the abnormal cloned group, but we didn’t find a difference in its expression.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of genome-wide gene expression and DNA methylation in abnormal cloned piglets

Jia

Zhao

et al. 2014

BMC Genomics

View full text Add to dashboard Cite

BackgroundEpigenetic modifications (especially altered DNA methylation) resulting in altered gene expression may be one reason for development failure or abnormalities in cloned animals, but the underlying mechanism of the abnormal phenotype in cloned piglets remains unknown. Some cloned piglets in our study showed abnormal phenotypes such as large tongue (longer and thicker), weak muscles, and exomphalos. Here we conducted DNA methylation (DNAm) immunoprecipitation and high throughput sequencing (MeDIP-seq) and RNA sequencing (RNA-seq) of muscle tissues of cloned piglets to investigate the relationship of abnormal DNAm with gene dysregulation and the unusual phenotypes in cloned piglets.ResultsAnalysis of the methylomes revealed that abnormal cloned piglets suffered more hypomethylation than hypermethylation compared to the normal cloned piglets, although the DNAm level in the CpG Island was higher in the abnormal cloned piglets. Some repetitive elements, such as SINE/tRNA-Glu Satellite/centr also showed differences. We detected 1,711 differentially expressed genes (DEGs) between the two groups, of which 243 genes also changed methylation level in the abnormal cloned piglets. The altered DNA methylation mainly affected the low and silently expressed genes. There were differences in both pathways and genes, such as the MAPK signalling pathway, the hypertrophic cardiomyopathy pathway, and the imprinted gene PLAGL1; all of which may play important roles in development of the abnormal phenotype.ConclusionsThe abnormal cloned piglets showed substantial changes both in the DNAm and the gene expression. Our data may provide new insights into understanding the molecular mechanisms of the reprogramming of genetic information in cloned animals.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-811) contains supplementary material, which is available to authorized users.

show abstract

Beckwith–Wiedemann syndrome in sibs discordant for IC2 methylation

Cited by 6 publications

References 26 publications

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Dysregulation of genome-wide gene expression and DNA methylation in abnormal cloned piglets

Contact Info

Product

Resources

About