Wiedemann‐Beckwith syndrome: Further prenatal characterization of the condition

We describe three unrelated cases of Wiedemann‐Beckwith syndrome (WBS). Two of them were diagnosed postnatally while the third was detected during pregnancy that resulted in elective termination. Amniotic karyotypes were normal in all. PCR amplification of polymorphic loci mapping to 11p15.5 region documented partial trisomy of 11p15.5 due to paternal translocation in one, and segmental and mosaic segmental unipaternal disomy (UPD) in the second and third cases, respectively. Based on findings documented in these cases and the literature, we tabulated the anomalies that might be detected prenatally by ultrasound and that may suggest the syndrome. Constant findings included fetal overgrowth, polyhydramios, enlarged placenta, and specifically a distended abdomen. As most described signs developed after 22 weeks of gestation, a careful follow‐up should be carried on until late stages of pregnancy. An amniotic karyotype might not detect subtle chromosomal rearrangements. We therefore recommend utilizing PCR of polymorphic loci on 11p15.5, in addition to conventional cytogenetic analysis of the fetus and both parents to detect possible maternal deletions or inversions, paternal duplications, and UPD that may account for the largest subset of sporadic WBS reaching 25% of cases. An early diagnosis of WBS is important for counseling the parents concerning potential risk for developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, and prevention of neonatal hypoglycemia. © 2001 Wiley‐Liss, Inc.     

Excess functional copy of allele at chromosomal region 11p15 may cause Widemann-Beckwith (EMG) syndrome

Wiedemann-Beckwith syndrome (WBS) is a genetic disorder with overgrowth and predisposition to Wilms' tumor. The putative locus of the gene responsible for this syndrome is assigned to chromosome region 11p15.5, and genomic imprinting in this region has been proposed: the paternally derived gene(s) at 11p15.5 is selectively expressed, while the maternally transmitted gene(s) is inactive. We examined 18 patients for the parental origin of their 11p15 regions. DNA polymorphism analyses using 6 loci on chromosome 11 showed that 2 patients with duplications of 11p15 regions from their respective fathers and one from the mother, indicating the transmission of an excessive paternal gene at 11p15 to each patient. Our results, together with the previous findings in karyotypically normal or abnormal patients and in overgrowth mouse experiments, are consistent with imprinting hypothesis that overexpression of paternally derived gene(s) at 11p15.5, probably the human insulin-like growth factor II (IGF-II) gene, may cause the phenotype. Total constitutional uniparental paternal disomy (UPD) or segmental UPD for the 6 loci examined of chromosome 11 was not observed in our 12 sporadic patients. In order to explain completely the inheritance of this syndrome in patients with various chromosomal constitutions, we propose an alternative imprinting mechanism involving the other locus that may be paternally imprinted and may suppress the expression of this gene. © 1994 Wiley-Liss, Inc.     

Proportion of cells with paternal 11p15 uniparental disomy correlates with organ enlargement in Wiedemann-beckwith syndrome

"Genetic mosaicism" describes the presence of two or more populations of cells within a single individual that differ in their genomic constitution. Although the occurrence of asymmetric overgrowth in Wiedemann-Beckwith syndrome (WBS) suggests that mosaicism has some role in the WBS phenotype, no direct evidence for this has been published. WBS is a congenital overgrowth syndrome with variable phenotype linked to the imprinted gene cluster on chromosome region 11p15. We have performed a molecular survey of multiple organs and tissues in a case of WBS with a high degree of mosaic paternal 11p15 uniparental disomy (UPD). The organs most severely affected were those with the highest percentage of cells with UPD. In particular there was a striking difference in the degree of mosaicism for 11p15 UPD between the extremely enlarged left adrenal and non-enlarged right adrenal gland. This result indicates that the proportion of paternal 11p15 UPD cells correlates with the tissue phenotype of WBS. Our results suggest that high proportions of abnormal cells result from a combination of stochastic events and cell selection. Mosaicism may explain the variable phenotypes including hemihyperplasia and predisposition to childhood cancers in WBS patients.     

Proportion of cells with paternal 11p15 uniparental disomy correlates with organ enlargement in Wiedemann‐Beckwith syndrome

“Genetic mosaicism” describes the presence of two or more populations of cells within a single individual that differ in their genomic constitution. Although the occurrence of asymmetric overgrowth in Wiedemann‐Beckwith syndrome (WBS) suggests that mosaicism has some role in the WBS phenotype, no direct evidence for this has been published. WBS is a congenital overgrowth syndrome with variable phenotype linked to the imprinted gene cluster on chromosome region 11p15. We have performed a molecular survey of multiple organs and tissues in a case of WBS with a high degree of mosaic paternal 11p15 uniparental disomy (UPD). The organs most severely affected were those with the highest percentage of cells with UPD. In particular there was a striking difference in the degree of mosaicism for 11p15 UPD between the extremely enlarged left adrenal and non‐enlarged right adrenal gland. This result indicates that the proportion of paternal 11p15 UPD cells correlates with the tissue phenotype of WBS. Our results suggest that high proportions of abnormal cells result from a combination of stochastic events and cell selection. Mosaicism may explain the variable phenotypes including hemihyperplasia and predisposition to childhood cancers in WBS patients. Am. J. Med. Genet. 92:111–116, 2000. © 2000 Wiley‐Liss, Inc.     

Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. The major features are anterior abdominal wall defects, macroglossia, and gigantism and less commonly neonatal hypoglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy and embryonal tumours occur. 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, and uniparental disomy (UPD) for chromosome 11 has been reported in sporadic cases. We investigated the incidence, pathogenesis, and clinical associations of UPD in 49 patients with non-familial BWS and a normal karyotype. UPD for chromosome 11p15 was detected in nine of 32 (28%) informative patients. A further two patients appeared to be disomic at the WT1 locus in chromosome 11p13, but were uninformative at chromosome 11p15.5 loci tested. In all cases with UPD the affected person was mosaic for a paternal isodisomy and a normal cell line indicating that UPD had arisen as a postzygotic event. Compared to cases in which paternal isodisomy for chromosomes 11p15.5 had been excluded (n = 23), BWS patients with UPD was more likely to have hemihypertrophy (6/9 versus 1/23, p < 0.001) and less likely to have exomphalos (0/9 versus 13/23, p < 0.01), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS.     

Seven cases of Wiedemann-Beckwith syndrome,including the first reported case of mosaic paternal isodisomy along the whole chromosome 11

Genomic imprinting of chromosome arm 11p is involved in the Wiedemann-Beckwith syndrome (WBS). About 20% of patients with sporadic WBS have paternal uniparental disomy (UPD) of 11p. Mitotic recombination at the 11p region has been suggested to be responsible for the somatic mosaicism in these patients. Our current study concerning sporadic WBS patients demonstrated six patients with mosaic isodisomy restricted to part of 11p and one patient with mosaic paternal uniparental disomy for the whole chromosome 11. Apparently the clinical findings for this patient did not differ from data reported for other WBS patients. This case makes it unlikely that the proximal short arm and the long arm of chromosome 11 contain imprinted genes with a phenotype recognizable prenatally or in infancy, and gives some support to the hypothesis that non-mosaic UPD-11 is prenatally lethal. Am. J. Med. Genet. 79:347–353, 1998. © 1998 Wiley-Liss, Inc.     

Paternal uniparental disomy of chromosome 14: confirmation of a clinically-recognizable phenotype

We report on a girl with a dicentric chromosome 14 [45,XX,inv(9)(p11q13),dic(14;14)(p11.1;p11.1)] with paternal uniparental disomy (UPD) for chromosome 14. Clinical findings include severe hypotonia, thoracic dystrophy, diastasis recti, swallowing difficulties with aspiration, developmental delay, and multiple minor anomalies. UPD for chromosome 14 has been documented with paternal UPD much less commonly than with maternal UPD. There have been ten cases of paternal UPD for chromosome 14 and one case of segmental paternal isodisomy of chromosome 14. Many of the findings are nonspecific, but the radiographic rib findings (referred to as the "coat-hanger" sign) are characteristic for this condition. UPD 14 studies should be performed in children thought to have Jeune asphyxiating thoracic dystrophy or other related osteochondrodysplasias when the diagnosis is in question. Our patient and the previously reported cases support a discrete recognizable phenotype for paternal UPD for chromosome 14.     

MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment

Human chromosome 11p15.5 harbours a large cluster of imprinted genes. Different epigenetic defects at this locus have been associated with both Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). Multiple techniques (Southern blotting, COBRA and microsatellite analysis) have been used so far to detect various DNA methylation abnormalities, uniparental disomies and copy number variations, which are characteristics of these two diseases. We have now evaluated a methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) for the molecular diagnosis of BWS and SRS. Seventy-three samples derived from BWS- and SRS-affected individuals and 20 controls were analysed by conventional tests and MS-MLPA in blind. All cases that were found positive with conventional methods were also identified by MS-MLPA. These included cases with paternal UPD11, hyper- or hypo-methylation at the Imprinting Centre 1 or Imprinting Centre 2 and rare 11p15.5 duplications. In summary, this MS-MLPA assay can detect both copy number variations and methylation defects of the 11p15.5 critical region within one single experiment and represents an easy, low cost and reliable system for the molecular diagnostics of BWS and SRS.     

Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome.

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.     

Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased tumor risk. BWS can be associated with genetic and/or epigenetic alterations that modify imprinted gene expression on chromosome 11p15.5. Somatic mosaicism for paternal uniparental disomy (UPD) of chromosome 11p15, found in 20% of BWS patients, is associated with specific features of BWS including hemihyperplasia, Wilms tumor, and hepatoblastoma. The highly variable phenotypic spectrum of BWS associated with UPD may well reflect the level of UPD 11 cells in specific organs and tissues such that very high levels of UPD might produce a more severe phenotypic expression of BWS. In this regard we report on two patients with severe presentations of BWS and extremely high levels of UPD in DNA from lymphocytes. Clinically, both patients demonstrated extreme macroglossia, persistent hypoglycemia, cardiomyopathy, hemihyperplasia, renal abnormalities, abdominal organomegaly, hepatoblastoma and died in the first 6 months of life. These two patients support the hypothesis that high levels of UPD define high expressivity in BWS.     

Linkage study in families with posterior helical ear pits and Wiedemann-Beckwith syndrome.

The Wiedemann-Beckwith syndrome (WBS) is defined by a group of anomalies, including macrosomia, macroglossia, omphalocele, and ear creases. Several minor anomalies have also been reported in the syndrome, including posterior helical ear pits (PHEP). Two independent linkage studies of pedigrees with autosomal dominant inheritance have shown linkage of WBS to 11p15.5 markers. Further confirming the location of WBS to this location is the finding of 11p15.5 duplications and translocations, as well as uniparental disomy for a small area of 11p15.5. In this study, members of previously described families exhibiting autosomal dominant inheritance of the PHEP phenotype were genotyped for three markers in the 11p15.5 region. These three markers were in the insulin-like growth factor (IGF2), insulin (INS), and tyrosine hydroxylase (TH) region. The data were examined by linkage analysis using the same genetic model used previously to demonstrate linkage of WBS to markers on chromosome 11p15.5: an autosomal dominant model with a penetrance of 0.90 and a gene frequency of 0.001. In one large pedigree, linkage analysis of the 11p15.5 markers excluded the PHEP phenotype from the IGF2, INS, and TH region. In the four other pedigrees examined, the marker loci were not sufficiently informative or the pedigrees did not provide sufficient power to exclude linkage from this region. The strongest evidence against linkage of the PHEP phenotype to 11p15.5 was evident by inspection of the segregation of the haplotypes of the markers in the pedigrees. In two informative pedigrees, relatives with the PHEP phenotype did not share the same haplotype of markers identical by descent. Our results show that the PHEP phenotype is not linked to chromosome 11p15.5 in the informative families tested. In the families examined, there are not enough individuals with WBS to determine if WBS was linked to 11p15.5 in these families. Although locus heterogeneity has not been demonstrated in WBS, it is possible that a second WBS locus exists and that the PHEP phenotype in these families is linked to a second WBS locus. Alternatively, the PHEP phenotype may occur independently of WBS so that the association of WBS and PHEP in our pedigrees may, in fact, represent causal heterogeneity.     

Linkage study in families with posterior helical ear pits and Wiedemann‐Beckwith Syndrome

The Wiedemann‐Beckwith syndrome (WBS) is defined by a group of anomalies, including macrosomia, macroglossia, omphalocele, and ear creases. Several minor anomalies have also been reported in the syndrome, including posterior helical ear pits (PHEP). Two independent linkage studies of pedigrees with autosomal dominant inheritance have shown linkage of WBS to 11p15.5 markers. Further confirming the location of WBS to this location is the finding of 11p15.5 duplications and translocations, as well as uniparental disomy for a small area of 11p15.5. In this study, members of previously described families exhibiting autosomal dominant inheritance of the PHEP phenotype were genotyped for three markers in the 11p15.5 region. These three markers were in the insulin‐like growth factor (IGF2), insulin (INS), and tyrosine hydroxylase (TH) region. The data were examined by linkage analysis using the same genetic model used previously to demonstrate linkage of WBS to markers on chromosome 11p15.5: an autosomal dominant model with a penetrance of 0.90 and a gene frequency of 0.001. In one large pedigree, linkage analysis of the 11p15.5 markers excluded the PHEP phenotype from the IGF2, INS, and TH region. In the four other pedigrees examined, the marker loci were not sufficiently informative or the pedigrees did not provide sufficient power to exclude linkage from this region. The strongest evidence against linkage of the PHEP phenotype to 11p15.5 was evident by inspection of the segregation of the haplotypes of the markers in the pedigrees. In two informative pedigrees, relatives with the PHEP phenotype did not share the same haplotype of markers identical by descent. Our results show that the PHEP phenotype is not linked to chromosome 11p15.5 in the informative families tested. In the families examined, there are not enough individuals with WBS to determine if WBS was linked to 11p15.5 in these families. Although locus heterogeneity has not been demonstrated in WBS, it is possible that a second WBS locus exists and that the PHEP phenotype in these families is linked to a second WBS locus. Alternatively, the PHEP phenotype may occur independently of WBS so that the association of WBS and PHEP in our pedigrees may, in fact, represent causal heterogeneity. © 2001 Wiley‐Liss, Inc.     

Allelic methylation of H19 and IGF2 in the Beckwith -- Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) Is a congenital overgrowthsyndrome with associated embryonal tumours. Most BWS cases aresporadic but familial cases occur In 15% of patients and inthese there is linkage to chromosome 11p15. In addition, a smallnumber of patients have cytogenetic abnormalities involvingchromosome 11 p15. Approximately 20% of sporadic BWS patientshave uniparental paternal dlsomy (UPD) of chromosome 11 p15.This finding together with the observation that penetrance infamilial cases depends on parental transmission, suggests thatthe gene(s) for BWS are imprinted. The recent demonstrationof blallellc expression of the otherwise maternally imprintedIGF2 gene In some BWS patients implicates excess IGF2 expressionin the disease. Here we have analysed the allele-specific methylationpatterns In the IGF2 gene and in the neighbouring and reciprocallyImprinted H19 gene in a group of 42 BWS patients, 10 of whichwere mosaic UPD cases. We found that allelic methylation ofboth genes was normal in all non-UPD cases, with the paternalallele being methylated, and was Increased In UPD cases in proportionwith the disomlc lineage. These findings suggest that sporadicBWS is not associated with a general alteration of methylationimprinting of the IGF2 and H19 genes. The methylation assayused in this study thus also offers a simple and reliable diagnostictest of UPD for 11p15.5. An unexpected finding was a distortionof the frequency of AvaU alleles at the IGF2 locus exclusivelyin UPD BWS cases (P < 0.001). This further Implicates theIGF2 gene in aspects of the BWS phenotype.     

Non-random X chromosome inactivation in an affected twin in a monozygotic twin pair discordant for Wiedemann-Beckwith syndrome

Wiedemann-Beckwith syndrome (WBS) is a syndrome including exomphalos, macroglossia, and generalized overgrowth. The locus has been assigned to 11p15.5, and genomic imprinting may play a part in the expression of one or more genes involved. Most cases are sporadic. An excess of female monozygotic twins discordant for WBS have been reported, and it has been proposed that this excess could be related to the process of X chromosome inactivation. We have therefore studied X chromosome inactivation in 13-year-old monozygotic twin girls who were discordant for WBS. In addition, both twins had Tourette syndrome. The twins were monochorionic and therefore the result of a late twinning process. This has also been the case in previously re-ported discordant twin pairs with infor-mation on placentation. X chromosome inactivation was determined in DNA from peripheral blood cells by PCR analysis at the androgen receptor locus. The affected twin had a completely skewed X inactiva-tion, where the paternal allele was on the active X chromosome in all cells. The unaf-fected twin had a moderately skewed X in-activation in the same direction, whereas the mother had a random pattern. Further studies are necessary to establish a possible association between the expression of WBS and X chromosome inactivation. © 1995 Wiley-Liss, Inc.     

Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith–Wiedemann syndrome and ovarian steroid cell tumour

Uniparental disomy (UPD) of single chromosomes is a well-known molecular aberration in a group of congenital diseases commonly known as imprinting disorders (IDs). Whereas maternal and/or paternal UPD of chromosomes 6, 7, 11, 14 and 15 are associated with specific IDs (Transient neonatal diabetes mellitus, Silver–Russell syndrome, Beckwith–Wiedemann syndrome (BWS), upd(14)-syndromes, Prader–Willi syndrome, Angelman Syndrome), the other autosomes are not. UPD of the whole genome is not consistent with life, in case of non-mosaic genome-wide paternal UPD (patUPD) it leads to hydatidiform mole. In contrast, mosaic genome-wide patUPD might be compatible with life. Here we present a 19-year-old woman with BWS features and initially diagnosed to be carrier of a mosaic patUPD of chromosome 11p15. However, the patient presented further clinical findings not typically associated with BWS, including nesidioblastosis, fibroadenoma, hamartoma of the liver, hypoglycaemia and ovarian steroid cell tumour. Additional molecular investigations revealed a mosaic genome-wide patUPD. So far, only nine cases with mosaic genome-wide patUPD and similar clinical findings have been reported, but these patients were nearly almost diagnosed in early childhood. Summarising the data from the literature and those from our patient, it can be concluded that the mosaic genome-wide patUPD (also known as androgenic/biparental mosaicism) might explain unusual BWS phenotypes. Thus, these findings emphasise the need for multilocus testing in IDs to efficiently detect cases with disturbances affecting more than one chromosome.     

47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.     

Uniparental disomy at chromosome 11p15.5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome

Costello syndrome (CS; MIM 218040) is characterized by short stature, facial dysmorphism, cardiac defects and predisposition to embryonal rhabdomyosarcoma (CS/ERMS) and other neoplasias. CS is caused by germline mutations in the HRAS gene on chromosome 11p15.5, a region showing allelic imbalances in sporadic ERMS and CS/ERMS. The critical gene for ERMS development in this region is unknown. The association of CS and ERMS as well as previous reports illustrating that somatic HRAS mutations are found in a proportion of these tumors prompted us to clarify the significance and a possible correlation of HRAS mutations and genomic rearrangements at 11p15.5 in sporadic ERMS. We screened for somatic HRAS mutations and 11p15.5 imbalances in six sporadic ERMS samples. This analysis uncovered five ERMS samples with uniparental disomy (UPD) at the HRAS locus, two of which harbored HRAS mutations. By analyzing informative genetic variations in or at the HRAS gene locus, we show that one HRAS allele is entirely lost in specimens with UPD at 11p15.5. Notably, in both cases with UPD and HRAS mutations these mutations were heterozygous. Therefore, they must have succeeded the emergence of UPD. In contrast, HRAS germline mutations are the first step in CS/ERMS. Subsequent development of UPD at 11p15.5 may explain previous observations that CS/ERMS express mutant HRAS only. These data implicate that in sporadic ERMS, UPD at 11p15.5 is not driven by HRAS mutations and that imbalances at 11p15.5 and HRAS mutations represent independent but cooperating events during ERMS development.     

A novel microdeletion in the IGF2/H19 imprinting centre region defines a recurrent mutation mechanism in familial Beckwith-Wiedemann syndrome

The overgrowth disorder Beckwith-Wiedemann syndrome (BWS) is associated with dysregulation of imprinted genes at chromosome 11p15.5. The molecular defects are heterogeneous but most of the cases are associated with defective DNA methylation at either one of two Imprinting Control Regions (IC1 and IC2) or Uniparental paternal Disomy (UPD) at 11p15.5. In rare cases, the BWS phenotype has been found associated with maternal transmission of IC1 microdeletions. We describe a family with a novel 1.8 kb deletion that is associated with hypermethylation at IC1. The mutation results from recombination between highly homologous sequences containing target sites for the zinc-finger protein CTCF (CTSs). This finding supports the hypothesis that the function of IC1 and the penetrance of the clinical phenotype depend on the spacing of the CTSs resulting from recombination in the mutant allele.     

Paternal uniparental isodisomy for chromosome 14 in a patient with a normal 46,XY karyotype

Chromosome 14 demonstrates imprinting with differing phenotypes for both maternal and paternal uniparental disomy (UPD). Although only 11 cases of paternal uniparental disomy 14 (patUPD14) have been reported, a distinct clinically recognizable syndrome has emerged. The major features are polyhydramnios, small thorax, mildly short limbs, abdominal wall defects, and characteristic face with short palpebral fissures, broad flat nasal bridge, prominent philtrum, and small ears. Radiographically, the chest is bell-shaped and the ribs are distinctive with caudal bowing anteriorly and cranial bowing posteriorly. Several affected infants have died from respiratory failure. The survivors have short stature and mental retardation. The initial cases were all recognized because of translocations involving chromosome 14. Subsequently, several patients with a similar phenotype and normal chromosomes have been reported, including two with mixed iso- and hetero-disomy as well as one with segmental UPD14. Our patient is the first with pure paternal isodisomy 14 in the absence of a translocation. We present additional clinical information, review the literature, and discuss mechanisms that may explain paternal isodisomy 14 in our chromosomally normal patient. Paternal UPD14 with normal karyotype may be more common than previously suspected and may be overlooked unless recognition of the clinical phenotype prompts investigation for UPD.     

A clinical, cytogenetic, and molecular study of 40 adults with the Prader-Willi syndrome.

A clinical, cytogenetic, and molecular study has been carried out on 40 adults with a firm diagnosis of Prader-Willi syndrome. A cytogenetically detectable deletion was observed in 58% while further subjects had a deletion which was detectable by molecular methods only, giving a total of 76%. Four cases of maternal uniparental disomy (UPD) were all female. Three of them were heterodisomic while the fourth was isodisomic. Two male probands were heterozygous at all loci tested yet did not have UPD. Although methylation studies showed that one of them had a single band using probe PW71, the other one had two bands. Psychiatric studies suggest that females with maternal UPD are indistinguishable psychologically from those with a paternal deletion in 15q11q13.