Beckwith-Wiedemann Syndrome

Overview

Overview: Beckwith-Wiedemann Syndrome (BWS) is a growth regulation disorder characterised by macrosomia (large body size) , macroglossia (large tongue), hemihyperplasia (some parts of the body are larger on one side) and kidney abnormalities - often diagnosed at birth. Children with BWS have an increased risk of developing childhood tumors (estimated at 7.5% of cases), usually before age 10: Wilms Tumor, Hepatoblastoma, Adrenocortical carcinoma, Rhabdomyosarcoma, and Neuroblastoma.

BWS is linked to genetic and epigenetic abnormalities of an area of chromosome 11 (11p15.5), which includes the CDKN1C and IGF2 genes. Most cases of BWS (about 85%) are sporadic (non-inherited, occurring by chance). Some cases of BWS (between 10-15%) are inherited in an autosomal dominant pattern. Overall incidence is estimated to be 1 out of 13,700 population (Weksberg et al, 2010).

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Infant
  • Cyclin-Dependent Kinase Inhibitor p57
  • Beckwith-Wiedemann syndrome
  • Pedigree
  • Mutation
  • Repressor Proteins
  • Neuroblastoma
  • Chromosome Aberrations
  • Nuclear Proteins
  • Restriction Fragment Length Polymorphism
  • DNA Methylation
  • Wilms Tumour
  • Alleles
  • Base Sequence
  • Childhood Cancer
  • Uniparental Disomy
  • Chromosome Mapping
  • Potassium Channels, Voltage-Gated
  • Membrane Proteins
  • Molecular Sequence Data
  • Chromosome Deletion
  • Transcription
  • Phenotype
  • Genomic Imprinting
  • Rhabdomyosarcoma
  • RNA, Untranslated
  • Trisomy
  • Zinc Fingers
  • Long Noncoding RNA
  • Chromosome 11
  • Pregnancy
  • Kidney Cancer
  • Telomere
  • Genotype
  • IGF2
  • Translocation
  • Genetic Predisposition
  • Newborns
  • Pregnancy Complications
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (6)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
IGF2 11p15.5 IGF-II, PP9974, C11orf43 Epigenetics
-IGF2 and Beckwith-Wiedemann Syndrome
105
CDKN1C 11p15.5 BWS, WBS, p57, BWCR, KIP2, p57Kip2 -CDKN1C and Beckwith-Wiedemann syndrome
16
KCNQ1OT1 11p15 LIT1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 -KCNQ1OT1 and Beckwith-Wiedemann syndrome
14
WT2 11p15.5 ADCR, MTACR1 -WT2 and Beckwith-Wiedemann syndrome
7
KCNQ1 11p15.5 LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1 -KCNQ1 and Beckwith-Wiedemann syndrome
6
SLC22A18 11p15.5 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Beckwith-Wiedemann syndrome
2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful Links (7 links)

Latest Publications

Fryssira H, Amenta S, Kanber D, et al.
A novel large deletion of the ICR1 region including H19 and putative enhancer elements.
BMC Med Genet. 2015; 16:30 [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2.
CASE PRESENTATION: A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion.
CONCLUSIONS: We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2 allele in both affected family members may reflect the active state of the normally silenced maternal IGF2 copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.

Adams DJ, Clark DA
Common genetic and epigenetic syndromes.
Pediatr Clin North Am. 2015; 62(2):411-26 [PubMed] Related Publications
Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.

Chen Z, Hagen DE, Elsik CG, et al.
Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.
Proc Natl Acad Sci U S A. 2015; 112(15):4618-23 [PubMed] Article available free on PMC after 14/10/2015 Related Publications
Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day ∼105 Bos taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS.

Eggermann T, Binder G, Brioude F, et al.
CDKN1C mutations: two sides of the same coin.
Trends Mol Med. 2014; 20(11):614-22 [PubMed] Related Publications
Cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) negatively regulates cellular proliferation and it has been shown that loss-of-function mutations in the imprinted CDKN1C gene (11p15.5) are associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS). With recent reports of gain-of-function mutations of the PCNA domain of CDKN1C in growth-retarded patients with IMAGe syndrome or Silver-Russell syndrome (SRS), its key role for growth has been confirmed. Thereby, the last gap in the spectrum of molecular alterations in 11p15.5 in growth-retardation and overgrowth syndromes could be closed. Recent functional studies explain the strict association of CDKN1C mutations with clinically opposite phenotypes and thereby contribute to our understanding of the function and regulation of the gene in particular and epigenetic regulation in general.

Mussa A, Pagliardini S, Pagliardini V, et al.
α-Fetoprotein assay on dried blood spot for hepatoblastoma screening in children with overgrowth-cancer predisposition syndromes.
Pediatr Res. 2014; 76(6):544-8 [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) and hemihyperplasia (HH) are overgrowth conditions with predisposition to hepatoblastoma for which early diagnosis patients undergo cancer screening based on determination of the tumor marker α-fetoprotein (αFP). Repeated blood draws are a burden for patients with consequent compliance issues and poor adherence to surveillance protocol. We sought to analyze feasibility and reliability of αFP dosage using an analytical micromethod based on blood dried on filter paper (DBS).
METHODS: Overall 143 coupled αFP determinations on plasma and DBS collected simultaneously were performed, of which 31 were in patients with hepatoblastoma predisposition syndromes and 112 were in controls. The plasma αFP dosage method was adapted to DBS adsorbed on paper matrix for newborn screening.
RESULTS: There was strong correlation between plasmatic and DBS αFP (r2 = 0.999, P < 0.001). Cohen's k coefficient for correlation was 0.96 for diagnostic cut-off of 10 U/ml (P < 0.001), commonly employed in clinical practice. The measurements on plasma and DBS were highly overlapping and consistent.
CONCLUSION: The DBS method allowed to dose αFP reliably and consistently for the concentrations commonly employed in clinical settings for the screening of hepatoblastoma, opening new scenarios about conducting cancer screening in overgrowth syndromes.

Kerns SL, Guevara-Aguirre J, Andrew S, et al.
A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.
J Clin Endocrinol Metab. 2014; 99(10):E2117-22 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
CONTEXT: CDKN1C, a cyclin-dependent kinase inhibitor and negative regulator of cellular proliferation, is paternally imprinted and has been shown to regulate β-cell proliferation. CDKN1C mutations are associated with growth disorders, including Beckwith-Wiedemann syndrome and IMAGe syndrome.
OBJECTIVE: To investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.
DESIGN, SETTING, AND PARTICIPANTS: Genomic DNA samples (15 affected and 26 unaffected from a six-generation pedigree) were analyzed by genome-wide single nucleotide polymorphism arrays, whole exome and Sanger sequencing, and multiplex ligation-dependent probe amplification.
MAIN OUTCOME MEASURE(S): Subjects were assessed for height, weight, adrenal gland size, ACTH, diabetes status, and testis volume. Linkage and sequence analyses were performed, and the identified genetic variant was functionally evaluated in reconstitution studies.
RESULTS: The pedigree followed a paternally imprinted pattern of inheritance, and genetic linkage analysis identified a single significant 2.6-megabase locus on chromosome 11p15, within the imprinting center region 2. Multiplex ligation-dependent probe amplification did not detect copy number variants or methylation abnormalities. Whole exome sequencing revealed a single novel variant in the proliferating cell nuclear antigen-binding region of CDKN1C (c.842G>T, p.R281I) that co-segregated with affected status and, unlike variants found in IMAGe, did not entirely abrogate proliferating cell nuclear antigen binding. Clinical assessments revealed that affected individuals had low testicular volume but normal adrenal function.
CONCLUSIONS: We report a novel CDKN1C mutation associated with features of IMAGe syndrome, but without adrenal insufficiency or metaphyseal dysplasia, and characterized by early-adulthood-onset diabetes. Our data expand the range of phenotypes observed with CDKN1C defects and suggest that CDKN1C mutations may represent a novel monogenic form of diabetes.

Demars J, Shmela ME, Khan AW, et al.
Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.
J Med Genet. 2014; 51(8):502-11 [PubMed] Related Publications
BACKGROUND: Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS; MIM 130650) and the Silver-Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor.
METHODS: We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively.
RESULTS: We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif.
CONCLUSIONS: This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.

Abi Habib W, Azzi S, Brioude F, et al.
Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome.
Hum Mol Genet. 2014; 23(21):5763-73 [PubMed] Related Publications
Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort of BWS patients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57 BWS patients with isolated ICR1 GOM and analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case in BWS patients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/SOX2 protects against methylation at local sites. These findings add new insights to the mechanism of the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM.

Massah S, Hollebakken R, Labrecque MP, et al.
Epigenetic characterization of the growth hormone gene identifies SmcHD1 as a regulator of autosomal gene clusters.
PLoS One. 2014; 9(5):e97535 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Regulatory elements for the mouse growth hormone (GH) gene are located distally in a putative locus control region (LCR) in addition to key elements in the promoter proximal region. The role of promoter DNA methylation for GH gene regulation is not well understood. Pit-1 is a POU transcription factor required for normal pituitary development and obligatory for GH gene expression. In mammals, Pit-1 mutations eliminate GH production resulting in a dwarf phenotype. In this study, dwarf mice illustrated that Pit-1 function was obligatory for GH promoter hypomethylation. By monitoring promoter methylation levels during developmental GH expression we found that the GH promoter became hypomethylated coincident with gene expression. We identified a promoter differentially methylated region (DMR) that was used to characterize a methylation-dependent DNA binding activity. Upon DNA affinity purification using the DMR and nuclear extracts, we identified structural maintenance of chromosomes hinge domain containing -1 (SmcHD1). To better understand the role of SmcHD1 in genome-wide gene expression, we performed microarray analysis and compared changes in gene expression upon reduced levels of SmcHD1 in human cells. Knock-down of SmcHD1 in human embryonic kidney (HEK293) cells revealed a disproportionate number of up-regulated genes were located on the X-chromosome, but also suggested regulation of genes on non-sex chromosomes. Among those, we identified several genes located in the protocadherin β cluster. In addition, we found that imprinted genes in the H19/Igf2 cluster associated with Beckwith-Wiedemann and Silver-Russell syndromes (BWS & SRS) were dysregulated. For the first time using human cells, we showed that SmcHD1 is an important regulator of imprinted and clustered genes.

Maeda T, Higashimoto K, Jozaki K, et al.
Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations.
Genet Med. 2014; 16(12):903-12 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
PURPOSE: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined.
METHODS: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced.
RESULTS: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR.
CONCLUSION: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

Chen CP, Su YN, Chen SU, et al.
Prenatal diagnosis of hypomethylation at KvDMR1 and Beckwith-Wiedemann syndrome in a pregnancy conceived by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer.
Taiwan J Obstet Gynecol. 2014; 53(1):90-4 [PubMed] Related Publications
OBJECTIVE: We report prenatal diagnosis of hypomethylation at KvDMR1 and Beckwith-Wiedemann syndrome (BWS) in a pregnancy conceived by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer.
CASE REPORT: A 34-year-old, primigravid woman was referred to the hospital at 21 weeks' gestation because of advanced maternal age and an isolated omphalocele in the fetus. Her husband had the fertility problem of oligospermia. This pregnancy was achieved by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer. Prenatal ultrasound revealed a 2.1 cm × 1.6 cm isolated omphalocele. The woman underwent amniocentesis. Array comparative genomic hybridization and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were applied to the DNA extracted from the uncultured amniocytes. Conventional cytogenetic analysis and high-resolution melting analysis were performed on cultured amniocytes. Array comparative genomic hybridization revealed no genomic imbalance. MS-MLPA analysis revealed H19DMR(IC1) normal methylation and KvDMR1(IC2) hypomethylation. Conventional cytogenetic analysis revealed a karyotype of 46,XX. High-resolution melting analysis using a methylation-specific polymerase chain reaction assay confirmed normal methylation at H19DMR(IC1) and hypomethylation at KvDMR1(IC2). The altered methylation status at 11p15.5 and the phenotype of omphalocele were consistent with the diagnosis of BWS.
CONCLUSION: In case of prenatally detected omphalocele associated with an obstetric history of assisted reproductive technology, a differential diagnosis of BWS should be considered. Methylation assays such as MS-MLPA and methylation-specific polymerase chain reaction using uncultured amniocytes are useful for rapid diagnosis of BWS under such circumstances.

Zarate YA, Shur N, Robin A, et al.
Persistent congenital hyperinsulinism in two patients with Beckwith-Wiedemann syndrome due to mosaic uniparental disomy 11p.
J Pediatr Endocrinol Metab. 2014; 27(9-10):951-5 [PubMed] Related Publications
Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism.

Uyar A, Seli E
The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders.
Curr Opin Obstet Gynecol. 2014; 26(3):210-21 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
PURPOSE OF REVIEW: Genomic imprinting refers to preferential allele-specific gene expression. DNA methylation-based molecular mechanisms regulate establishment and maintenance of parental imprints during early embryo development and gametogenesis. Because of the coincident timing, a potential association between assisted reproductive technology (ART) procedures and imprinting defects has been investigated in various studies. In this review, we provide an overview of genomic imprinting and present a summary of the relevant clinical data.
RECENT FINDINGS: ART procedures affect DNA methylation pattern, parental imprinting status, and imprinted gene expression in the mouse embryo. In humans, several case series suggested an association between ART and imprinting disorders, with a three-fold to six-fold higher prevalence of ART use among children born with Beckwith-Wiedemann syndrome compared to the general population. However, more recent studies failed to support these findings and could not demonstrate an association between imprinting disorders and ARTs, independent of subfertility.
SUMMARY: ART procedures may affect methylation status of imprinted regions in the DNA, leading to imprinting disorders. Although the low prevalence of imprinting disorders makes it challenging to perform conclusive clinical trials, further studies in large registries are required to determine the real impact of ARTs on their occurrence.

Alders M, Maas SM, Kadouch DJ, et al.
Methylation analysis in tongue tissue of BWS patients identifies the (EPI)genetic cause in 3 patients with normal methylation levels in blood.
Eur J Med Genet. 2014 May-Jun; 57(6):293-7 [PubMed] Related Publications
The Beckwith-Wiedemann syndrome is caused by disturbed imprinting of genes at 11p15.5. Routine diagnostic testing for Beckwith-Wiedemann syndrome (BWS) includes methylation analysis of the imprinting centers ICR1 and ICR2 in DNA extracted from lymphocytes. In approximately 15% of BWS patients the diagnosis cannot be molecularly confirmed. In this study we determined the methylation status in resected tongue tissue of 11 BWS patients and compared this to the genetic defects found by routine diagnostic screening of blood lymphocytes. In all three patients with normal methylation levels in blood, aberrant methylation patterns were found in tongue tissue. In two patients a UPD was detected and the third case had hypermethylation of ICR1. This result shows that tissue specific mosaic (epi)genetic changes, not present in blood, is the underlying defect in at least a subset of BWS patients without a molecular diagnosis after standard genetic testing.

Eggermann T, Heilsberg AK, Bens S, et al.
Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing.
J Mol Med (Berl). 2014; 92(7):769-77 [PubMed] Related Publications
UNLABELLED: The chromosomal region 11p15 contains two imprinting control regions (ICRs) and is a key player in molecular processes regulated by genomic imprinting. Genomic as well as epigenetic changes affecting 11p15 are associated either with Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS). In the last years, a growing number of patients affected by imprinting disorders (IDs) have reported carrying the disease-specific 11p15 hypomethylation patterns as well as methylation changes at imprinted loci at other chromosomal sites (multi-locus methylation defects, MLMD). Furthermore, in several patients, molecular alterations (e.g., uniparental disomies, UPDs) additional to the primary epimutations have been reported. To determine the frequency and distribution of mutations and epimutations in patients referred as SRS or BWS for genetic testing, we retrospectively ascertained our routine patient cohort consisting of 711 patients (SRS, n = 571; BWS, n = 140). As this cohort represents the typical cohort in a routine diagnostic lab without clinical preselection, the detection rates were much lower than those reported from clinically characterized cohorts in the literature (SRS, 19.9%; BWS, 28.6%). Among the molecular subgroups known to be predisposed to MLMD, the frequencies corresponded to that in the literature (SRS, 7.1% in ICR1 hypomethylation carriers; BWS, 20.8% in ICR2 hypomethylation patients). In several patients, more than one epigenetic or genetic disturbance could be identified. Our study illustrates that the complex molecular alterations as well as the overlapping and sometimes unusual clinical findings in patients with imprinting disorders (IDs) often make the decision for a specific imprinting disorder test difficult. We therefore suggest to implement molecular assays in routine ID diagnostics which allow the detection of a broad range of (epi)mutation types (epimutations, UPDs, chromosomal imbalances) and cover the clinically most relevant known ID loci because of the following: (a) Multi-locus tests increase the detection rates as they cover numerous loci. (b) Patients with unexpected molecular alterations are detected. (c) The testing of rare imprinting disorders becomes more efficient and quality of molecular diagnosis increases. (d) The tests identify MLMDs. In the future, the detailed characterization of clinical and molecular findings in ID patients will help us to decipher the complex regulation of imprinting and thereby providing the basis for more directed genetic counseling and therapeutic managements in IDs.
KEY MESSAGE: Molecular disturbances in patients with imprinting disorders are often not restricted to the disease-specific locus but also affect other chromosomal regions. These additional disturbances include methylation defects, uniparental disomies as well as chromosomal imbalances. The identification of these additional alterations is mandatory for a well-directed genetic counseling. Furthermore, these findings help to decipher the complex regulation of imprinting.

Docherty LE, Rezwan FI, Poole RL, et al.
Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes.
J Med Genet. 2014; 51(4):229-38 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.
DESIGN: We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith-Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.
RESULTS: We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver-Russell syndrome presentations and one with pseudohypoparathyroidism 1B.
CONCLUSIONS: This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.

Brioude F, Lacoste A, Netchine I, et al.
Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance.
Horm Res Paediatr. 2013; 80(6):457-65 [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM).
AIM: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis.
RESULTS: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors.
CONCLUSION: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

Azzi S, Abi Habib W, Netchine I
Beckwith-Wiedemann and Russell-Silver Syndromes: from new molecular insights to the comprehension of imprinting regulation.
Curr Opin Endocrinol Diabetes Obes. 2014; 21(1):30-8 [PubMed] Related Publications
PURPOSE OF REVIEW: The imprinted human 11p15.5 region encompasses two imprinted domains important for the control of fetal growth: the H19/IGF2 domain in the telomeric region and the KCNQ1OT1/CDKN1C domain in the centromeric region. These two domains are differentially methylated and each is regulated by its own imprinting control region (ICR): ICR1 in the telomeric region and ICR2 in the centromeric region. Aberrant methylation of the 11p15.5 imprinted region, through genetic or epigenetic mechanisms, leads to two clinical syndromes, with opposite growth phenotypes: Russell-Silver Syndrome (RSS; with severe fetal and postnatal growth retardation) and Beckwith-Wiedemann Syndrome (BWS; an overgrowth syndrome).
RECENT FINDINGS: In this review, we discuss the recently identified molecular abnormalities at 11p15.5 involved in RSS and BWS, which have led to the identification of cis-acting elements and trans-acting regulatory factors involved in the regulation of imprinting in this region. We also discuss the multilocus imprinting disorders identified in various human syndromes, their clinical outcomes and their impact on commonly identified metabolism disorders.
SUMMARY: These new findings and progress in this field will have direct consequence for diagnostic and predictive tools, risk assessment and genetic counseling for these syndromes.

Higashimoto K, Jozaki K, Kosho T, et al.
A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.
Clin Genet. 2014; 86(6):539-44 [PubMed] Related Publications
The IGF2/H19-imprinting control region (ICR1) functions as an insulator to methylation-sensitive binding of CTCF protein, and regulates imprinted expression of IGF2 and H19 in a parental origin-specific manner. ICR1 methylation defects cause abnormal expression of imprinted genes, leading to Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS). Not only ICR1 microdeletions involving the CTCF-binding site, but also point mutations and a small deletion of the OCT-binding site have been shown to trigger methylation defects in BWS. Here, mutational analysis of ICR1 in 11 BWS and 12 SRS patients with ICR1 methylation defects revealed a novel de novo point mutation of the OCT-binding site on the maternal allele in one BWS patient. In BWS, all reported mutations and the small deletion of the OCT-binding site, including our case, have occurred within repeat A2. These findings indicate that the OCT-binding site is important for maintaining an unmethylated status of maternal ICR1 in early embryogenesis.

Baskin B, Choufani S, Chen YA, et al.
High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome.
Hum Genet. 2014; 133(3):321-30 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15 %) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification. Molecular alterations were detected in 167 patients, where 103 (62 %) showed loss of methylation at IC2, 23 (14 %) had gain of methylation at IC1, and 41 (25 %) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9 %) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counseling.

Denomme MM, Mann MR
Maternal control of genomic imprint maintenance.
Reprod Biomed Online. 2013; 27(6):629-36 [PubMed] Related Publications
Genomic imprinting is a specialized transcriptional phenomenon that employs epigenetic mechanisms to facilitate parental-specific expression. Perturbations in parental epigenetic asymmetry can lead to the development of imprinting disorders, such as Beckwith-Wiedemann syndrome and Angelman syndrome. DNA methylation is one of the most widely studied epigenetic marks that characterizes imprinted regions. During gametogenesis and early embryogenesis, imprinted methylation undergoes a cycle of erasure, acquisition and maintenance. Gamete and embryo manipulations for the purpose of assisted reproduction are performed during these reprogramming events and may lead to their disruption. Recent studies point to the role of maternal-effect proteins in imprinted gene regulation. Studies are now required to increase understanding of how these factors regulate genomic imprinting as well as how assisted reproduction technologies may alter their function.

Calvello M, Tabano S, Colapietro P, et al.
Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome.
Epigenetics. 2013; 8(10):1053-60 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p<0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75-86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55-59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD.

Keren B, Chantot-Bastaraud S, Brioude F, et al.
SNP arrays in Beckwith-Wiedemann syndrome: an improved diagnostic strategy.
Eur J Med Genet. 2013; 56(10):546-50 [PubMed] Related Publications
Beckwith-Wiedemann syndrome is an overgrowth disorder with an increased risk of childhood tumors that results from a dysregulation of imprinted gene expression in the 11p15 region. Since epigenetic defects are the most frequent anomalies, first-line diagnostic methods involve methylation analysis. When paternal isodisomy is suspected, it should be confirmed by a second technique capable of distinguishing true 11p15 paternal disomy (patUPD) from paternal 11p15 duplication or 11p15 trisomy. We sought to evaluate the interest of using SNP arrays in the Beckwith-Wiedemann syndrome diagnostic strategy. We analyzed the SNP profiles of 25 Beckwith Wiedemann patients with previously determined methylation indexes. Among them, 3 had 11p15 trisomies, 13 had patUPD, 8 had an inconclusive methylation index and 1 had a normal result. All known trisomies and known patUPDs were detected. Moreover we found 7 low-rate mosaicisms 11p15 patUPDs among the 8 patients with an inconclusive methylation index. We were able to precisely characterize the sizes and mosaicism rates of the anomalies. We demonstrate that SNP arrays are of real diagnostic interest in Beckwith-Wiedemann syndrome: 1) they help to distinguish patUPDs from trisomies more precisely than karyotyping and FISH, 2) they help determine the size and mosaicism rate of patUPDs, 3) they provide complementary information in inconclusive cases, helping to distinguish low-rate patUPD mosaicism from other BWS-related molecular defects.

Sakaguchi R, Okamura E, Matsuzaki H, et al.
Sox-Oct motifs contribute to maintenance of the unmethylated H19 ICR in YAC transgenic mice.
Hum Mol Genet. 2013; 22(22):4627-37 [PubMed] Related Publications
Abnormal methylation at the maternally inherited H19 imprinted control region (H19 ICR) is one of the causative alterations leading to pathogenesis of Beckwith-Wiedemann syndrome (BWS). Recently, it was shown in human BWS patients, as well as mouse cell culture experiments, that Sox-Oct motifs (SOM) in the H19 ICR might play a role in protecting the maternal ICR from de novo DNA methylation. By grafting a mouse H19 ICR fragment into a human β-globin yeast artificial chromosome (YAC) followed by analysis in transgenic mice (TgM), we showed previously that the fragment carried sufficient information to establish and maintain differential methylation after fertilization. To examine possible functions of the SOM in the establishment and/or maintenance of differential methylation, two kinds of YAC-TgM were generated in this study. In the ΔSOM TgM, carrying the mouse H19 ICR bearing an SOM deletion, a maternally inherited transgenic ICR exhibited increased levels of methylation around the deletion site, in comparison to the wild-type control, after implantation. In the λ + CTCF + b (LCb) TgM, carrying a 2.3 kb λ DNA fragment supplemented with the fragment b including the SOM and four CTCF binding sites, maternally and some of the paternally inherited LCb fragments were significantly less methylated when compared with a control λ + CTCF fragment that was supplemented only with additional CTCF sites; the λ + CTCF was substantially methylated regardless of the parent of origin after implantation. These results demonstrated that the SOM in the maternal H19 ICR was required for maintaining surrounding sequences in the unmethylated state in vivo.

Lee BH, Kim GH, Oh TJ, et al.
Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.
J Hum Genet. 2013; 58(9):604-10 [PubMed] Related Publications
Methylation-specific (MS) multiplex ligation-dependent probe amplification (MLPA) at two differentially methylated regions (DMRs) at chromosome 11p15, H19-DMR and LIT1-DMR, and microsatellite analysis for uniparental disomy (UPD) at chromosome 7 or 11, have been recommended for the genetic diagnosis of the Beckwith-Wiedemann syndrome (BWS) and the Silver-Russell syndrome (SRS). In this study, the efficacy of the MS pyrosequencing method at H19-DMR and LIT1-DMR at 11p15 and SGCE-DMR at 7q21 was evaluated for the genetic diagnosis of BWS (n=18) and SRS (n=20) patients. Epigenetic alterations or UPD were detected in 83% of BWS and 50% of SRS individuals by MS-MLPA, but the detection rate increased to 95% of BWS and 70% of SRS by MS pyrosequencing. Thirteen BWS patients (72%) harbored loss-of-methylation (LOM) at LIT1-DMR and two patients (11%) harbored gain-of-methylation (GOM) at H19-DMR, whereas two patients (11%) had both LOM at LIT1-DMR and GOM at H19-DMR, reflecting paternal UPD 11. Thirteen SRS patients (65%) harbored LOM at H19-DMR, whereas one patient (5%) had GOM at SGCE-DMR, reflecting maternal UPD 7. Birth anthropometric profiles were significantly correlated to methylation scores at either H19-DMR or LIT1-DMR. In conclusion, MS pyrosequencing enhanced the detection rate of molecular defects in BWS and SRS. Moreover, it indicates that methylation status at 11p15.5 might have an important role in fetal growth.

Chen Z, Robbins KM, Wells KD, Rivera RM
Large offspring syndrome: a bovine model for the human loss-of-imprinting overgrowth syndrome Beckwith-Wiedemann.
Epigenetics. 2013; 8(6):591-601 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a human loss-of-imprinting syndrome primarily characterized by macrosomia, macroglossia, and abdominal wall defects. BWS has been associated with misregulation of two clusters of imprinted genes. Children conceived with the use of assisted reproductive technologies (ART) appear to have an increased incidence of BWS. As in humans, ART can also induce a similar overgrowth syndrome in ruminants which is referred to as large offspring syndrome (LOS). The main goal of our study is to determine if LOS shows similar loss-of-imprinting at loci known to be misregulated in BWS. To test this, Bos taurus indicus × Bos taurus taurus F1 hybrids were generated by artificial insemination (AI; control) or by ART. Seven of the 27 conceptuses in the ART group were in the > 97th percentile body weight when compared with controls. Further, other characteristics reported in BWS were observed in the ART group, such as large tongue, umbilical hernia, and ear malformations. KCNQ1OT1 (the most-often misregulated imprinted gene in BWS) was biallelically-expressed in various organs in two out of seven overgrown conceptuses from the ART group, but shows monoallelic expression in all tissues of the AI conceptuses. Furthermore, biallelic expression of KCNQ1OT1 is associated with loss of methylation at the KvDMR1 on the maternal allele and with downregulation of the maternally-expressed gene CDKN1C. In conclusion, our results show phenotypic and epigenetic similarities between LOS and BWS, and we propose the use of LOS as an animal model to investigate the etiology of BWS.

Dias RP, Maher ER
Genes, assisted reproductive technology and trans-illumination.
Epigenomics. 2013; 5(3):331-40 [PubMed] Related Publications
Genomic imprinting is a parent-of-origin allele-specific epigenetic process that is critical for normal development and health. The establishment and maintenance of normal imprinting is dependent on both cis-acting imprinting control centers, which are marked by differentially (parental allele specific) methylated marks, and trans mechanisms, which regulate the establishment and/or maintenance of the correct methylation epigenotype at the imprinting control centers. Studies of rare human imprinting disorders such as familial hydatidiform mole, Beckwith-Wiedemann syndrome and familial transient neonatal diabetes mellitus have enabled the identification of genetic (e.g., mutations in KHDC3L [C6ORF221], NLRP2 [NALP2], NLRP7 [NALP7] and ZFP57) and environmental (assisted reproductive technologies) factors that can disturb the normal trans mechanisms for imprinting establishment and/or maintenance. Here we review the clinical and molecular aspects of these imprinting disorders in order to demonstrate how the study of rare inherited disorders can illuminate the molecular characteristics of fundamental epigenetic processes, such as genomic imprinting.

Soejima H, Higashimoto K
Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.
J Hum Genet. 2013; 58(7):402-9 [PubMed] Related Publications
Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.

Kalkan E, Waguespack SG
Endocrine tumors associated with neurofibromatosis type 1, Peutz-Jeghers syndrome and other familial neoplasia syndromes.
Front Horm Res. 2013; 41:166-81 [PubMed] Related Publications
Endocrine tumors are a less common but important component of the clinical spectrum of a number of hereditary tumor syndromes such as neurofibromatosis type 1, Peutz-Jeghers syndrome, Beckwith-Wiedemann syndrome, the tuberous sclerosis complex, Li-Fraumeni syndrome, PTEN hamartoma tumor syndrome, and APC-associated polyposis. It is important to recognize the often unique clinical presentations of these tumors and possible strategies for presymptomatic screening and early diagnosis.

Choufani S, Shuman C, Weksberg R
Molecular findings in Beckwith-Wiedemann syndrome.
Am J Med Genet C Semin Med Genet. 2013; 163C(2):131-40 [PubMed] Related Publications
Our understanding of Beckwith-Wiedemann syndrome (BWS) has recently been enhanced by advances in its molecular characterization. These advances have further delineated intricate (epi)genetic regulation of the imprinted gene cluster on chromosome 11p15.5 and the role of these genes in normal growth and development. Studies of the molecular changes associated with the BWS phenotype have been instrumental in elucidating critical molecular elements in this imprinted region. This review will provide updated information on the multiple new regulatory elements that have been recently found to contribute to in cis or in trans control of imprinted gene expression in the chromosome 11p15.5 region and the clinical expression of the BWS phenotype.

Weksberg R, Shuman C, Beckwith JB
Beckwith-Wiedemann syndrome.
Eur J Hum Genet. 2010; 18(1):8-14 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.

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