The Experts below are selected from a list of 2664 Experts worldwide ranked by ideXlab platform
Eamonn R Maher - One of the best experts on this subject based on the ideXlab platform.
-
Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome).
PLOS Genetics, 2009Co-Authors: Esther Meyer, Shanaz Pasha, Fatimah Rahman, John R.w. Yates, C. Geoffrey Woods, Eamonn R MaherAbstract:Beckwith-Wiedemann Syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.
-
mitotic recombination and uniparental disomy in beckwith wiedemann Syndrome
Genomics, 2007Co-Authors: Wendy N Cooper, Rebecca Curley, Fiona Macdonald, Eamonn R MaherAbstract:Beckwith-Wiedemann Syndrome (BWS) is a model human imprinting disorder resulting from altered activity of one or more genes in the 11p15.5 imprinted gene cluster. Approximately 20% of BWS cases have uniparental disomy (UPD) of chromosome 11. Such cases appear to result from mitotic recombination occurring in early embryogenesis and offer a rare opportunity to study mitotic recombination in nonneoplastic cells. We analyzed a cohort of 52 children with BWS and UPD using a panel of microsatellite markers for chromosome 11. All cases demonstrated mosaic paternal isodisomy, and IGF2 and H19 were included in the segment of UPD in all cases. However, the extent of segmental disomy was variable, with no evidence of clustering of the proximal UPD breakpoint. In most cases (92% of those informative) UPD did not involve 11q, but 4 patients demonstrated UPD for the whole of chromosome 11. In contrast to meiotic recombination, the mitotic recombination frequency did not decline near the centromere.
-
beckwith wiedemann Syndrome and assisted reproduction technology art
Journal of Medical Genetics, 2003Co-Authors: Eamonn R Maher, Wendy N Cooper, Fiona Macdonald, Louise Brueton, Sarah Bowdin, A Luharia, Trevor Cole, Julian Roy Sampson, Christopher L R Barratt, Wolf ReikAbstract:Beckwith-Wiedemann Syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5.1 The classical clinical features of BWS are macroglossia, pre- and/or postnatal overgrowth, and anterior abdominal wall defects (umbilical hernia or exomphalos). Additional more variable features include hemihypertrophy, neonatal hypoglycaemia, facial naevus flammeus, ear pits and creases, renal anomalies, and an increased risk of embryonal tumours.2 Most cases of BWS are sporadic and ∼20% of these have uniparental disomy (paternal isodisomy) for a variable region of chromosome 11 which always includes the 11p15.5 imprinted gene cluster.3–5 Up to 60% of sporadic BWS patients have epigenetic changes at differentially methylated regions within 11p15.5 that are associated with alterations in the imprinting or expression of paternally expressed genes, such as IGF2 and KCNQ1OT , or maternally expressed genes, such as H19 and CDKN1C .1 Thus, 5–10% have epigenetic alterations at the IGF2 / H19 loci (the maternal H19 and IGF2 alleles display paternal allele methylation and expression patterns with biallelic IGF2 expression and silencing of H19 expression),6 and 40–50% have loss of maternal allele methylation at a differentially methylated region (KvDMR1) within an intron of KCNQ1 . KvDMR1 loss of methylation is associated with biallelic expression of KCNQ1OT .7–9 The epigenetic alterations at H19 / IGF2 or KvDMR1 are thought to result from defects at two putative imprinting control centres (BWSIC1 and BWSIC2, respectively).1 The precise nature of the putative BWSIC2 is unknown and therefore the origin of these putative BWSIC2 defects is unknown. Weksberg et al 10 showed a clear association between monozygotic twinning and BWS with KvDMR1 loss of methylation and suggested two possible explanations: (1) that discordance for BWS in monozygotic twins is caused by unequal splitting of the inner cell mass …
-
epigenetic modification and uniparental inheritance of h19 in beckwith wiedemann Syndrome
Journal of Medical Genetics, 1997Co-Authors: Daniel Catchpoole, Paul N Schofield, Wayne W K Lam, D Valler, I K Temple, Johanna A Joyce, Wolf Reik, Eamonn R MaherAbstract:Beckwith-Wiedemann Syndrome (BWS) is a congenital overgrowth Syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS.
Andrew P Feinberg - One of the best experts on this subject based on the ideXlab platform.
-
children with idiopathic hemihypertrophy and beckwith wiedemann Syndrome have different constitutional epigenotypes associated with wilms tumor
American Journal of Human Genetics, 2005Co-Authors: Emily L Niemitz, Andrew P Feinberg, Sheri Brandenburg, Paul E Grundy, Michael R DebaunAbstract:Idiopathic hemihypertrophy (IH) is a congenital overgrowth Syndrome associated with an increased risk of embryonal cancers in childhood. A related developmental disorder is Beckwith-Wiedemann Syndrome (BWS), which increases risk for embryonal cancers, including Wilms tumor. Constitutional epigenetic alterations associated with BWS have been well characterized and include epigenetic alterations of imprinted genes on 11p15. The frequency of hypermethylation of H19 in children with IH and Wilms tumor, 20% (3/15), was significantly lower than the frequency in children with BWS and Wilms tumor, 79% (11/14; P = .0028). These results indicate that children with IH and Wilms tumor have different constitutional epigenotypes from those of children with BWS and Wilms tumor.
-
microdeletion of lit1 in familial beckwith wiedemann Syndrome
American Journal of Human Genetics, 2004Co-Authors: Emily L Niemitz, Mitsuo Oshimura, Michael R Debaun, Jonathan Fallon, Kazuhiro Murakami, Hiroyuki Kugoh, Andrew P FeinbergAbstract:Beckwith-Wiedemann Syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57KIP2 or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1, which is near p57KIP2, or H19/IGF2. Unlike Prader-Willi and Angelman Syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57KIP2, indicating deletion of an element important for the regulation of p57KIP2 expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans.
-
association of in vitro fertilization with beckwith wiedemann Syndrome and epigenetic alterations of lit1 and h19
American Journal of Human Genetics, 2003Co-Authors: Michael R Debaun, Emily L Niemitz, Andrew P FeinbergAbstract:Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth Syndrome—namely, Beckwith-Wiedemann Syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART—five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS—four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring Syndrome reported in ruminants.
-
low frequency of p57kip2 mutation in beckwith wiedemann Syndrome
American Journal of Human Genetics, 1997Co-Authors: Michael R Debaun, Stephen J Elledge, Gurvaneet S Randhawa, Betty A Reichard, Andrew P FeinbergAbstract:Summary Beckwith-Wiedemann Syndrome (BWS) is an autosomal dominant disorder of increased prenatal growth and predisposition to embryonal cancers such as Wilms tumor. BWS is thought to involve one or more imprinted genes, since some patients show paternal uniparental disomy, and others show balanced germ-line chromosomal rearrangements involving the maternal chromosome. We previously mapped BWS, by genetic linkage analysis, to 11p15.5, which we and others also found to contain several imprinted genes; these include the gene for insulin-like growth factor II (IGF2) and H19, which show abnormal imprint-specific expression and/ or methylation in 20% of BWS patients, and p57 KIP2 , a cyclin-dependent kinase inhibitor, which we found showed biallelic expression in one of nine BWS patients studied. In addition, p57 KIP2 was recently reported to show mutations in two of nine BWS patients. We have now analyzed the entire coding sequence and intron-exon boundaries of p57 KIP2 in 40 unrelated BWS patients. Of these patients, only two (5%) showed mutations, both involving frameshifts in the second exon. In one case, the mutation was transmitted to the proband's mother, who was also affected, from the maternal grandfather, suggesting that p57 KIP2 is not imprinted in at least some affected tissues at a critical stage of development and that haploinsufficiency due to mutation of either parental allele may cause at least some features of BWS. The low frequency of p57 KIP2 mutations, as well as our recent discovery of disruption of the K v LQT1 gene in patients with chromosomal rearrangements, suggest that BWS can involve disruption of multiple independent 11p15.5 genes.
-
human kvlqt1 gene shows tissue specific imprinting and encompasses beckwith wiedemann Syndrome chromosomal rearrangements
Nature Genetics, 1997Co-Authors: Maxwell P Lee, Laura A Johnson, Andrew P FeinbergAbstract:Genomic imprinting is an epigenetic chromosomal modification in the gamete or zygote causing preferential expression of a specific parental allele in somatic cells of the offspring. We and others have identified three imprinted human genes on 11p15.5, IGF2 (refs 1-4), H19 (refs 1,5), and p57KIP2 (ref. 6), although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other imprinted genes within this large interval. We previously mapped an embryonal tumour suppressor gene to this region7, as well as five balanced germline chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann Syndrome (BWS)8, a condition characterized by prenatal overgrowth and cancer. We isolated the upstream exons of the previously identified gene KVLQT1, which causes the familial cardiac defect long-QT (LQT) Syndrome. We found that KVLQT1 spans much of the interval between p57KIP2 and IGF2, and that it is also imprinted. We demonstrated that the gene is disrupted by chromosomal rearrangements in BWS patients, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumour. Furthermore, the lack of parent-of-origin effect in LQT Syndrome appears to be due to relative lack of imprinting in the affected tissue, cardiac muscle, representing a novel mechanism for variable penetrance of a human disease gene.
Michael R Debaun - One of the best experts on this subject based on the ideXlab platform.
-
children with idiopathic hemihypertrophy and beckwith wiedemann Syndrome have different constitutional epigenotypes associated with wilms tumor
American Journal of Human Genetics, 2005Co-Authors: Emily L Niemitz, Andrew P Feinberg, Sheri Brandenburg, Paul E Grundy, Michael R DebaunAbstract:Idiopathic hemihypertrophy (IH) is a congenital overgrowth Syndrome associated with an increased risk of embryonal cancers in childhood. A related developmental disorder is Beckwith-Wiedemann Syndrome (BWS), which increases risk for embryonal cancers, including Wilms tumor. Constitutional epigenetic alterations associated with BWS have been well characterized and include epigenetic alterations of imprinted genes on 11p15. The frequency of hypermethylation of H19 in children with IH and Wilms tumor, 20% (3/15), was significantly lower than the frequency in children with BWS and Wilms tumor, 79% (11/14; P = .0028). These results indicate that children with IH and Wilms tumor have different constitutional epigenotypes from those of children with BWS and Wilms tumor.
-
microdeletion of lit1 in familial beckwith wiedemann Syndrome
American Journal of Human Genetics, 2004Co-Authors: Emily L Niemitz, Mitsuo Oshimura, Michael R Debaun, Jonathan Fallon, Kazuhiro Murakami, Hiroyuki Kugoh, Andrew P FeinbergAbstract:Beckwith-Wiedemann Syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57KIP2 or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1, which is near p57KIP2, or H19/IGF2. Unlike Prader-Willi and Angelman Syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57KIP2, indicating deletion of an element important for the regulation of p57KIP2 expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans.
-
serum α fetoprotein screening for hepatoblastoma in children with beckwith wiedemann Syndrome or isolated hemihyperplasia
The Journal of Pediatrics, 2003Co-Authors: Carol L Clericuzio, Gail E. Tomlinson, Emily Chen, Dawn Elizabeth Mcneil, Timothy Oconnor, Elaine H Zackai, Livija Medne, Michael R DebaunAbstract:An elevated risk of hepatoblastoma for children with Beckwith-Wiedemann Syndrome or isolated hemihyperplasia is well established. We describe five children with Beckwith-Wiedemann Syndrome or isolated hemihyperplasia for whom serial serum α-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma.
-
association of in vitro fertilization with beckwith wiedemann Syndrome and epigenetic alterations of lit1 and h19
American Journal of Human Genetics, 2003Co-Authors: Michael R Debaun, Emily L Niemitz, Andrew P FeinbergAbstract:Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth Syndrome—namely, Beckwith-Wiedemann Syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART—five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS—four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring Syndrome reported in ruminants.
-
feasibility of partial nephrectomy for wilms tumor in children with beckwith wiedemann Syndrome who have been screened with abdominal ultrasonography
Journal of Pediatric Surgery, 2002Co-Authors: Elizabeth D Mcneil, Jacob C Langer, Peter L Choyke, Michael R DebaunAbstract:Abstract Background: Children with Beckwith-Wiedemann Syndrome (BWS), a congenital Syndrome associated with Wilms' tumor commonly are screened with abdominal sonography resulting in detection of tumor at a lower stage. Wilms' tumors have been traditionally treated with complete nephrectomy; however, smaller tumors are amenable to nephron-sparing surgery. Because Wilms' tumors may be metachronous and nonmalignant disease may compromise renal function in BWS, nephron-sparing approaches may be desirable as the first option. Methods: Seven patients with BWS and Wilms' tumor underwent nephrectomy. The preoperative computed tomography (CT) or ultrasound scan were evaluated by a pediatric surgeon to assess whether partial nephrectomy would have been feasible. The determining criteria included tumor involving one third or less of the kidney and no involvement of either hilar or vascular structures. Results: Seven patients underwent complete nephrectomies. The remaining patient, who had undergone a left nephrectomy before the initiation of screening had salvage chemotherapy after biopsy results showed right kidney involvement with Wilms' tumor. Conclusions: Nephron-sparing surgery is reasonable to consider in children with Beckwith-Wiedemann Syndrome who are screened at intervals of 4 months or less. The relative benefits of partial nephrectomy for children with Wilms' tumor–predisposing conditions only can be assessed in the setting of a cooperative clinical trial. J Pediatr Surg 37:57-60. Copyright © 2002 by W.B. Saunders Company.
Rosalind M. John - One of the best experts on this subject based on the ideXlab platform.
-
Fetal growth restriction in a genetic model of sporadic Beckwith–Wiedemann Syndrome
'The Company of Biologists', 2018Co-Authors: Simon J. Tunster, Mathew Van De Pette, Hugo D. J. Creeth, Louis Lefebvre, Rosalind M. JohnAbstract:Beckwith–Wiedemann Syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2, which is imprinted in mice but not in humans. To overcome this issue, we generated a novel model combining a truncation of distal chromosome 7 allele (DelTel7) with transgenic rescue of Ascl2 expression. This novel model recapitulated placentomegaly associated with BWS, but did not lead to fetal overgrowth
-
fetal overgrowth in the cdkn1c mouse model of beckwith wiedemann Syndrome
Disease Models & Mechanisms, 2011Co-Authors: Simon James Tunster, Mathew Van De Pette, Rosalind M. JohnAbstract:Mutations in the imprinted CDKN1C gene are associated with the childhood developmental disorder Beckwith-Wiedemann Syndrome (BWS). Multiple mouse models with deficiency of Cdkn1c recapitulate some aspects of BWS but do not exhibit overgrowth of the newborn, a cardinal feature of patients with BWS. In this study, we found that Cdkn1c mutants attained a 20% increase in weight during gestation but experienced a rapid reversal of this positive growth trajectory very late in gestation. We observed a marked effect on placental development concurrently with this loss of growth potential, with the appearance of large thrombotic lesions in the labyrinth zone. The trilaminar trophoblast layer that separates the maternal blood sinusoids from fetal capillaries was disordered with a loss of sinusoidal giant cells, suggesting a role for Cdkn1c in maintaining the integrity of the maternal-fetal interface. Furthermore, the overgrowth of mutant pups decreased in the face of increasing intrauterine competition, identifying a role for Cdkn1c in the allocation of the maternal resources via the placenta. This work explains one difficulty in precisely replicating BWS in this animal model: the differences in reproductive strategies between the multiparous mouse, in which intrauterine competition is high, and humans, in which singleton pregnancies are more common.
Wolf Reik - One of the best experts on this subject based on the ideXlab platform.
-
beckwith wiedemann Syndrome and assisted reproduction technology art
Journal of Medical Genetics, 2003Co-Authors: Eamonn R Maher, Wendy N Cooper, Fiona Macdonald, Louise Brueton, Sarah Bowdin, A Luharia, Trevor Cole, Julian Roy Sampson, Christopher L R Barratt, Wolf ReikAbstract:Beckwith-Wiedemann Syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5.1 The classical clinical features of BWS are macroglossia, pre- and/or postnatal overgrowth, and anterior abdominal wall defects (umbilical hernia or exomphalos). Additional more variable features include hemihypertrophy, neonatal hypoglycaemia, facial naevus flammeus, ear pits and creases, renal anomalies, and an increased risk of embryonal tumours.2 Most cases of BWS are sporadic and ∼20% of these have uniparental disomy (paternal isodisomy) for a variable region of chromosome 11 which always includes the 11p15.5 imprinted gene cluster.3–5 Up to 60% of sporadic BWS patients have epigenetic changes at differentially methylated regions within 11p15.5 that are associated with alterations in the imprinting or expression of paternally expressed genes, such as IGF2 and KCNQ1OT , or maternally expressed genes, such as H19 and CDKN1C .1 Thus, 5–10% have epigenetic alterations at the IGF2 / H19 loci (the maternal H19 and IGF2 alleles display paternal allele methylation and expression patterns with biallelic IGF2 expression and silencing of H19 expression),6 and 40–50% have loss of maternal allele methylation at a differentially methylated region (KvDMR1) within an intron of KCNQ1 . KvDMR1 loss of methylation is associated with biallelic expression of KCNQ1OT .7–9 The epigenetic alterations at H19 / IGF2 or KvDMR1 are thought to result from defects at two putative imprinting control centres (BWSIC1 and BWSIC2, respectively).1 The precise nature of the putative BWSIC2 is unknown and therefore the origin of these putative BWSIC2 defects is unknown. Weksberg et al 10 showed a clear association between monozygotic twinning and BWS with KvDMR1 loss of methylation and suggested two possible explanations: (1) that discordance for BWS in monozygotic twins is caused by unequal splitting of the inner cell mass …
-
transactivation of igf2 in a mouse model of beckwith wiedemann Syndrome
Nature, 1997Co-Authors: Fanglin Sun, Wendy Dean, Gavin Kelsey, Nicholas D Allen, Wolf ReikAbstract:The gene IGF2, which encodes a fetal insulin-like growth factor, is imprinted, so only one of two parental copies of the gene is expressed. The altered expression of IGF2 has been implicated in Beckwith-Wiedemann Syndrome, a human fetal overgrowth Syndrome, which is characterized by overgrowth of several organs and an increased risk of developing childhood tumours. We have introduced Igf2 transgenes into the mouse genome by using embryonic stem cells, which leads to transactivation of the endogenous Igf2 gene. The consequent overexpression of Igf2 results in most of the symptoms of Beckwith-Wiedemann Syndrome, including prenatal overgrowth, polyhydramnios, fetal and neonatal lethality, disproportionate organ overgrowth including tongue enlargement, and skeletal abnormalities. These phenotypes establish Igf2 overexpression as a key determinant of Beckwith-Wiedemann Syndrome.
-
epigenetic modification and uniparental inheritance of h19 in beckwith wiedemann Syndrome
Journal of Medical Genetics, 1997Co-Authors: Daniel Catchpoole, Paul N Schofield, Wayne W K Lam, D Valler, I K Temple, Johanna A Joyce, Wolf Reik, Eamonn R MaherAbstract:Beckwith-Wiedemann Syndrome (BWS) is a congenital overgrowth Syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS.