Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000–2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71–2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46–0.64), 1.04 (95% CI 0.92–1.17) and 0.30 (95% CI 0.24–0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19–5.36 per 1000), proportion prenatally diagnosed (50–100%) and proportion of prenatally diagnosed resulting in TOPFA (13–67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.     

Turner syndrome: evaluation of prenatal diagnosis in 19 European registries

This study evaluated the prenatal diagnosis of Turner syndrome by ultrasound examination in an unselected population from all over Europe. Data from 19 congenital malformation registries from 11 European countries were analyzed. Turner syndrome was diagnosed in 125 cases (7.2%) in a total of 1,738 chromosome abnormalities. Sixty-seven percent of cases were detected prenatally by ultrasound examination due to the presence of congenital defects. The most frequent anomalies were cystic hygroma (59.5%) and hydrops fetalis (19%). The most frequent karyotype was 45,X (81.6%) followed by different types of mosaicism (16.8%). Significant differences in congenital defects (P = 0.0003) were observed between 45,X karyotypes and 45,X mosaicism cases. Prenatal counseling for 45,X mosaicism should take into account the expectation of a milder phenotype. In 78.6% of cases diagnosed by ultrasound examination due to congenital anomalies, the pregnancy was terminated. Prenatal detection of Turner syndrome by ultrasound examination was high in this unselected population.     

Jacobsen and Beckwith–Wiedemann syndromes in a child with mosaicism for partial 11pter trisomy and partial 11qter monosomy

We report on a child with Jacobsen syndrome (JBS, OMIM 147791) and abnormalities consistent with Beckwith–Wiedemann syndrome (BWS, OMIM 130650). The constitutional karyotype was apparently normal, but FISH analysis with probes specific for the short and long arms of chromosome 11 found 11qter deletion with 11pter trisomy in 80% of the cells studied. Array‐CGH identified breakpoints in the 11p15.3 and 11q24.1 regions consistent with Jacobsen and Beckwith–Wiedemann syndromes. We suggest that this chromosome imbalance results from a pericentric inversion of chromosome 11 inherited from the father, with mosaicism resulting from meiotic recombination of a paternal inversion followed by mitotic recombination during the first embryonic divisions. This hypothesis is supported by the results of microsatellite marker analysis. Three previous cases of pericentric inversion and recombination of chromosome 11 have been reported. Our case is unusual in that it combines the Jacobsen and Beckwith–Wiedemann syndromes with mosaicism. © 2013 Wiley Periodicals, Inc.     

Prenatal stress reduces the effectiveness of the neurosteroid 3 alpha,5 alpha-THP to block kainic-acid-induced seizures

The effects of prenatal stress on the ability of the 5 alpha-reduced progesterone metabolite and neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) to prevent seizures was examined. On gestational Day 18, pregnant rats were exposed to 20 min of restraint stress (prenatal stress condition) or no such stress (control condition). The adult, gonadectomized offspring exposed to the prenatal stress or control condition were administered 0.0, 4.0, or 8.0 mg/kg 3 alpha,5 alpha-THP 1 hr prior to testing for kainic-acid-induced (32 mg/kg SC) ictal activity. The rats exposed to prenatal stress tended to have more partial seizures and significantly more tonic clonic seizures that were of longer duration than the no prenatal stress rats. Four mg/kg 3 alpha,5 alpha-THP was sufficient to significantly reduce seizure duration of no prenatal stress females, compared to the 0.0 mg/kg dosage of 3 alpha,5 alpha-THP. Seizure duration was reduced in no prenatal stress females by a dose of 4 mg/kg 3 alpha,5 alpha-THP, whereas a dose of 8 mg/kg was required to obtain comparable seizure reduction in prenatally stressed females and males in both groups. There was attrition following kainic-acid testing; of the 18 animals in each group originally, 9 prenatally stressed males, 6 prenatally stressed females, 6 nonprenatally stressed males and 5 nonprenatally stressed females were able to be tested in the water maze and perfused. One week after seizures, there were no differences in the water maze performance of the remaining animals. There were fewer cresyl violet-stained neurons in the CA3 region of the hippocampus of prenatally stressed rats compared to the nonprenatally stressed rats. Basal plasma corticosterone was greater in prenatally stressed animals, but this was due to increases in females rather than males. Plasma 3 alpha,5 alpha-THP was not significantly different in prenatally stressed males and females compared to their no prenatal stress counterparts. These data suggest that the sensitivity to, or responsiveness of, 3 alpha,5 alpha-THP to prevent seizures is decreased after prenatal stress, particularly in females.     

Meckel–Gruber Syndrome: a population-based study on prevalence,prenatal diagnosis,clinical features,and survival in Europe

Meckel–Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11–36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.     

Chest wall hamartoma with Wiedemann‐Beckwith syndrome: Clinical report and brief review of chromosome 11p15.5‐related tumors

A girl born with a left chest wall hamartoma, macroglossia, nevus flammeus of the middle forehead, and a small umbilical hernia developed left lower extremity hemihypertrophy by 1 year of age and is assumed to have Wiedemann‐Beckwith syndrome. Hamartoma of the bladder and a cardiac fibrous hamartoma have been reported previously in association with Wiedemann‐Beckwith syndrome. Infantile hamartomas are exceedingly rare and add to the spectrum of tumor formation in the syndrome. © 2001 Wiley‐Liss, Inc.     

Epidemiology of orofacial clefts in a Danish county over 35 years – Before and after implementation of a prenatal screening programme for congenital anomalies

In 2004 the Danish National Board of Health changed its screening recommendations. Since 2005 a first trimester screening for Down syndrome and a prenatal ultrasound screening for congenital anomalies in the second trimester of pregnancy has been offered to all pregnant women.The aim of this study was to describe the prevalence of cleft lip with or without cleft palate and cleft palate in a Danish area and to describe associated anomalies and the development in prenatal diagnosis over time. The study was based on data from the EUROCAT Registry for Funen County. The registry is based on multiple data sources and includes information about live births, fetal deaths with a gestational age >20 weeks and terminations of pregnancy after prenatal diagnosis of severe fetal anomaly. The study included all fetuses/infants out of a population of 182,907 births diagnosed with orofacial clefts born between 1980 and 2014. There were 271 cases diagnosed with cleft lip with or without cleft palate and 127 cases diagnosed with cleft palate, giving a prevalence of 14.8 per 10,000 births for cleft lip with or without cleft palate and 6.9 per 10,000 births for cleft palate. There were no significant changes in prevalence over time for the two anomalies, calculated with and without inclusion of genetic and chromosomal cases. Overall 66 cases were diagnosed prenatally (17% of total). For isolated cleft lip with or without cleft palate none of the 157 cases born before 2005 were diagnosed prenatally compared to 34 of 58 cases (59%) born in 2005–2014 (p?<?0.01). The proportion of liveborn infants with multiple congenital anomalies also changed after 2005 with 15% (39/266) of all liveborn infants with orofacial clefts born 1980–2004 having multiple anomalies compared to 7% (7/96) in 2005–2014 (p?<?0.05).The implementation of the new screening programme in 2005 has given a major change in prenatal detection rate and reduced the proportion of liveborn infants with orofacial clefts classified as multiple congenital anomaly cases. The prevalence of cleft lip with or without cleft palate was higher than reported from many other countries.     

Methylation analysis in tongue tissue of BWS patients identifies the (EPI)genetic cause in 3 patients with normal methylation levels in blood

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.     

Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.     

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.     

Effect of prenatal exposure to aromatase inhibitor, testosterone, or antiandrogen on the development of feminine sexual behavior in ferrets of both sexes

Experiments were conducted to assess the role of prenatal exposure of the brain to estrogen in controlling the development of proceptive and receptive feminine sexual behavior in ferrets of both sexes. Female ferrets, deprived prenatally of estrogen via maternal ovariectomy on gestational day 30 (42-day gestation) plus SC implantation of an aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), into their mothers, were significantly less receptive than control females when tested in adulthood after ovariectomy and administration of low (5 and 10 micrograms/kg) dosages of estradiol benzoate (EB). However, they were no less receptive than control females in response to a high (15 micrograms/kg) dosage of EB. Estrogen-deprived females showed EB-induced reductions in approach latencies to a stud male (proceptive responses) which were equivalent to those of control females. These results suggest that estrogenic stimulation of the female brain during fetal development enhances later receptive responsiveness to estradiol. However, prenatal estrogen appears not to be an absolute requirement for the development of receptive or proceptive coital capacity in females. In a previous study castrated male ferrets failed to show EB-induced reductions in the latency to approach a sexually active male, indicating that they were proceptively defeminized. In the present study females exposed prenatally to exogenous testosterone also failed to display significant EB-induced reductions in approach latencies to a sexually active male. Males deprived prenatally of estrogen ran faster to a stud male after adult administration of increasing dosages of EB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determinants of parental decisions after the prenatal diagnosis of Down syndrome

We evaluated demographic factors and factors specific to the current pregnancy, and their relationship to the decision to continue or terminate a pregnancy after prenatal diagnosis of Down syndrome. All cases of Down syndrome (DS) managed at a tertiary care center from 1989–1997 were retrospectively analyzed with respect to maternal age, parity, gestational age, sonographic findings, insurance status, and race. Of 145 cases of trisomy 21, 19 (13.1%) of women chose continuation of pregnancy, while 126 (86.9%) chose termination. There were no differences between groups in parity, sonographic findings, insurance status, or race at the time of diagnosis. However, patients who chose termination were significantly older and earlier in gestation than those electing to continue their pregnancy. When Down syndrome is diagnosed prenatally, the choice of termination is related to maternal age and gestational age, but only gestational age is a significant independent predictor of pregnancy termination. Am. J. Med. Genet. 79:172–174, 1998. © 1998 Wiley-Liss, Inc.     

Pregnancy outcome and prenatal diagnosis of sex chromosome abnormalities in Hawaii, 1986-1999

Sex chromosome abnormalities such as Turner syndrome, Klinefelter syndrome, triple X syndrome, and 47,XYY can be prenatally diagnosed and electively terminated. This investigation examined the pattern of pregnancy outcome of prenatally and postnatally diagnosed sex chromosome abnormalities in Hawaii during 1986-1999 and calculated prenatal diagnosis and subsequent elective termination rates for various factors. Data were obtained from a statewide population-based birth defects registry. The study included 205 detected sex chromosome abnormality cases of which 93 (45%) were live births, 18 (9%) late fetal deaths, 37 (18%) early fetal deaths, and 57 (28%) elective terminations. Pregnancy outcome distribution varied by type of sex chromosome abnormality. Prenatal diagnosis was reported for 132 (64%) of the cases, of which 46 (35%) were subsequently electively terminated. Eleven cases were elective terminations where the sex chromosome abnormality was diagnosed after delivery. Elective termination rates subsequent to prenatal diagnosis differed by sex chromosome abnormality, being highest for 45,X (54%), followed by 47,XXY (46%), 47,XYY (29%), and 47,XXX (17%). Although prenatal diagnosis rates increased significantly over the time period (P = 0.006), the subsequent elective termination rate declined slightly, albeit the trend was not statistically significant (P = 0.440). The prenatal diagnosis rate was highest for the 35-39-year maternal age group, although this age group did not have subsequent elective termination rates higher than other maternal age groups. Pregnancy outcome distribution and prenatal diagnosis and subsequent elective termination of sex chromosome abnormalities appeared to depend on the type of sex chromosome abnormality, year of delivery, and maternal age.     

Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries

The study was performed to evaluate the prevalence of prenatal ultrasound diagnoses for renal anomalies in 20 registries of 12 European countries, and to compare the different prenatal scanning policies. Standardized data were acquired from 709,030 livebirths, stillbirths, and induced abortions during the study period of 2.5 years and transmitted for central analysis. At least one renal malformation was diagnosed in 1130 infants and fetuses. Prenatal diagnosis (PD) was given in 81.8% of all cases, 29% of these pregnancies were terminated. The highest detection rate was reported for unilateral multicystic dysplastic kidneys with 97% (102/105). An early diagnosis was documented for exstrophy of bladder at a mean gestational age of 18.5 weeks. Dilatations of the upper urinary tract were seen late in pregnancy at 28.3 weeks. Terminations of pregnancies (TOP) were performed in 67% (58/86) of the detected bilateral renal agenesis/dysgenesis, but only 4% of the unilateral multicystic dysplastic renal malformations (4/102). In about 1/3 of the cases, renal malformations are within the category of associated malformations, which include multiple non-syndromal malformations, chromosomal aberrations, and non-chromosomal syndromes. Renal malformations were detected in 2/3 of the associated category by the first prenatal ultrasound scan. Detection rates vary in the different countries of the European community due to diverse policies, ethical, and religious background. Countries with no routine ultrasound show the lowest rates in detection, and termination of pregnancy. Prenatally detected renal malformations should result in a careful examination for further anomalies. Prenatal ultrasound fulfills the needs of screening examinations and is a good tool in detecting lethal and severe renal malformations.     

Prenatally detected fragile X females: long-term follow-up studies show high risk of mental impairment.

The prenatal detection of a positive fragile X [fra(X)] female raises difficult counseling issues. In order to address questions regarding the long term outlook, we have conducted follow-up studies on 4 fra(X) positive females which were carried to term. Three were prenatally detected, and one was a false negative. The subjects were between 3 and 7 years old when follow-up investigation of mental status was conducted. The first case age, 6 and 9/12 years, had an IQ of 106. On measures of achievement she had some difficulty with arithmetic. The second and third cases were clearly affected. They were judged to be mildly to moderately mentally retarded. The fourth case was borderline normal. The prenatal amniocentesis cytogenetic frequencies had a mean of 3.74% (range 0-8.5%). On postnatal follow-up testing of blood, the mean cytogenetic frequency increased to 31.75% (range 24-47%), an 8.5 fold increase. Follow-up DNA samples from 3 of the 4 subjects were analyzed for underlying DNA mutations using probe StB12.3 which detects insertions and methylation status of the FMR-1 gene. All 3 showed an affected female genotype with a large insert (greater than 500bp) and complete CpG island methylation. We conclude: (1) prenatally detected cytogenetic frequencies of females increase by an average 8.5 fold on follow-up postnatal studies, (2) genetic counseling should indicate the risks to be affected are approximately 75% when a positive female is prenatally detected, (3) DNA testing can help determine carrier status but may not accurately predict whether a female will be mentally affected.     

Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith–Wiedemann syndrome with epimutations

PurposeExpression 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.MethodsComprehensive 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.ResultsThirty-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.ConclusionMaternally 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.Genet Med16 12, 903–912.     

Genetic diagnoses and associated anomalies in fetuses prenatally diagnosed with esophageal atresia

Esophageal atresia (EA) is a congenital anomaly occurring in 2.3 per 10,000 live births. Due to advances in prenatal imaging, EA is more readily diagnosed, but data on the associated genetic diagnoses, other anomalies, and postnatal outcome for fetuses diagnosed prenatally with EA are scarce. We collected data from two academic medical centers (n = 61). Our data included fetuses with suspected EA on prenatal imaging that was confirmed postnatally and had at least one genetic test. In our cohort of 61 cases, 29 (49%) were born prematurely and 19% of those born alive died in the first 9 years of life. The most commonly associated birth defects were cardiac anomalies (67%) and spine anomalies (50%). A diagnosis was made in 61% of the cases; the most common diagnoses were vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula with esophageal atresia, radial or renal dysplasia, and limb anomalies association (43%, although 12% met only 2 of the criteria), trisomy 21 (5%), and CHARGE syndrome (5%). Our findings suggest that most fetuses with prenatally diagnosed EA have one or more additional major anomaly that warrants a more comprehensive clinical genetics evaluation. Fetuses diagnosed prenatally appear to represent a cohort with a worse outcome.     

Dominant inheritance of Wiedemann-Beckwith syndrome: further evidence for transmission of "unstable premutation" through carrier women

We report on a 4-generation family in which the Wiedemann Beckwith syndrome (WBS) was transmitted as an autosomal dominant trait. The condition occurred in sibs born to carrier women and in children born to affected mothers. Presumptive carrier women were examined for microsigns of WBS in an attempt to determine whether extreme variability of the disorder, rather than an unaffected carrier state, was present. No minor stigmata of the WBS could be found in the presumptive carriers. Our study supports a previous hypothesis that in some families the WBS can be transmitted in a 2-step process involving first an unstable premutation and then a "telomutation." Because only females appear to be transmitters of the telomutation, an ovum-mediated sex-associated factor may be involved in the process of telomutation.     

Prenatal detection of rare chromosomal autosomal abnormalities in Europe

The aim of the present study was to evaluate the prenatal detection of rare chromosomal autosomal abnormalities by ultrasound (US) examination. Data were obtained from 19 congenital malformation registries from 11 European countries, between 01/07/96 and 31/12/98. A total of 664,340 births were covered and 7,758 cases with congenital malformations were recorded. Rare autosomal abnormalities were diagnosed in 114 cases (6.6%) from a total of 1,738 chromosome abnormalities. There were a wide variety of autosomal abnormalities: the most common were deletions (33 cases), duplications (32 cases), trisomies of chromosomes 8, 9, 10, 14, 15, and 16 (23 cases), and unbalanced rearrangements (19 cases). Out of these cases, 45.6% were detected prenatally by US examination due to the presence of congenital anomaly. As for the types of chromosomal anomaly, unbalanced rearrangements and deletions were the most frequently detected by US. A high percentage of cases with balanced rearrangements were associated with severe congenital anomalies. The most frequent congenital anomalies detected by US were cystic hygroma (20.6%), central nervous system defects (17.6%), cardiac defects (13.2%), and diaphragm defects (10.3%). This large series offers useful information about prenatal diagnosis by US of congenital defects associated with rare autosomal abnormalities and it provides a valuable knowledge about outcome. Fetal anomalies detected by US that were associated with rare autosomal abnormalities were significantly more frequent than those associated with common chromosomal abnormalities (45.6 vs. 34.7%). This study indicates the need to increase the detection of congenital anomalies by US.     

SNP arrays in Beckwith–Wiedemann syndrome: An improved diagnostic strategy

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.