Detection and characterization of new genetic mutations in individuals heterozygous for lactate dehydrogenase-B(H) deficiency using DNA conformation polymorphism analysis and silver staining

In northwest European countries maternal age is increasing. This will lead to an increase of the prevalence of Down syndrome conceptuses. Meanwhile, the increased use of prenatal cytogenetic diagnosis (PCD) will lead to a decrease in the prevalence of Down syndrome among livebirths. We were interested to know what the result of these two opposite developments would be in the near future, and we describe here a model to quantify these processes and the resulting livebirth prevalence of Down syndrome. The model is demonstrated for The Netherlands from 1992 to 2001. The predicted livebirth prevalence for The Netherlands in 1992 is 1.36 per 1000. Demographic factors will cause an increase to 1.76 per 1000 in 2001 with present indications for PCD and a utilization ratio of 50%. An increase of the utilization ratio to 90% in 2001 will lead to a prevalence of 1.22 per 1000, a little less than the present prevalence. Alternative screening programs, including maternal serum screening, could lead to a further decrease of the livebirth prevalence. The model described here can be used for evaluation of the consequences of alternative forms of Down syndrome screening.     

Spontaneous abortion and subsequent Down syndrome livebirth

Summary Analyses of two data sets are presented, one based on nationwide hospital discharges for the USA for 1970–1971, the other for Upstate New York vital record data for 1976–1981. Summary relative risks of a Down syndrome livebirth were calculated within the three maternal age categories below 20, 20–29, and 30 years and above for those with a history of one spontaneous abortion and for those with a history of two or more, compared to those with no reported previous abortions. There was significant heterogeneity by age and reproductive history in the relative risk of an affected child. In general the trends revealed that the younger the mother and the more the number of abortions, the higher the relative risk of a Down syndrome livebirth compared to the rates for women of the same age for those with no previous abortions. Extrapolation from average maternal age specific rates on Down syndrome imply a rate per 1000 livebirths somewhere in the range of 1.1 to 11.4 for women under 20 years with a history of one spontaneous abortion, of 5.2 to 13.4 for women under 20 years with a history of two or more spontaneous abortions, and of 1.0 to 2.4 for women 20 to 29 years with a history of two or more spontaneous abortions. (Average background livebirth rates in women under 30 years are, in contrast, in the range of about 0.5 to 1.0 per 1000 and for the average woman aged 35 years, at which prenatal diagnosis is usually felt to be indicated, 2.7 per 1000.) For those in the other categories these data did not reveal clinically significant effects upon average maternal age specific rates. It is emphasized that because of limitations in the data it is not possible to refine these risks by adjusting for karyotype, the age at which the abortions occurred, or other biologic and social factors associated with embryonic and fetal death. The implications of the analyses here for genetic counseling should be regarded as preliminary and tentative.     

Down syndrome in British Columbia, 1952-73: incidence and mean maternal age.

Records of children with Down syndrome (DS) at the BC Health Surveillance Registry were linked to their Birth Registrations to derive maternal ages. Incidence and maternal-age specific rates were calculated for 1952-73. Mean maternal age has declined both for normal and DS children, the latter to a marked degree, so that in 1972-73 80% were born to women under 35 years. Using maternal age of 40 and over as an indication for amniocentesis would only detect 10% of DS children. The crude incidence rate (mean 1.28/1000 livebirths) has not changed appreciably over the study period except for 1969 in which a statistically significant peak occurred. The standarized rate showed an increasing trend but it is not clear whether this was a true biological increase or resulted from better ascertainment.     

Frequency of Down syndrome in livebirths by single-year maternal age interval: results of a Massachusetts study.

An analysis of rates of intra-state Down syndrome livebirths to Massachusetts residents by single-year maternal age interval in 1958-1965 inclusive was carried out. A gradual increase of rate of the Down syndrome occurred from age 20 to about age 31, and a steeper increase thereafter. Different regression equations were derived in the 20-31 and the 33-45 age group. The regression equations were ln y = 0.04515 x -1.45759 for those age 20-31 and ln y = 0.24302x-7.57870, for those age 33-45, where y = rate per 1,000 and x = maternal age. The regression-derived rates are slightly lower than those reported in similar analyses of data from Sweden and New York State, but they are not markedly discrepant.     

Epilepsy and Pregnancy: A Report from the Oxford Record Linkage Study

The files of the Oxford Record Linkage Study were used to identify 223 infants delivered to 168 epileptic women as the result of 218 pregnancies. There were six stillbirths, two of which were grossly malformed. It was shown that the population of epileptic mothers differed significantly from the total reproducing population in respect of social class. Each pregnancy resulting in a livebirth was therefore matched exactly for social class, civil status, maternal age, parity, hospital, and year of delivery with three control deliveries resulting in livebirths. The defects noted at birth were abstracted from the Record Linkage files, and any subsequent hospital admissions or deaths of the children were also abstracted.There were highly significant excesses of congenital abnormalities among the infants born to epileptic mothers (13·8% of livebirths had some degree of defect of congenital origin compared with 5·6% of controls, P <0·0005). It was shown that neither the frequency with which the mother had fits nor the length of time she had had the epilepsy seemed to bear any relation to the frequency of defects in the offspring—with the exception of the two mothers who developed epilepsy in the first     

Down syndrome rates and relaxed selection at older maternal ages.

Preferential survival in older mothers of fetuses with Down syndrome has been proposed as contributing to the maternal-age effect of this condition. If correct, this provocative hypothesis, which may be termed "relaxed selection," has major implications for approaches to prevention of Down syndrome live births in older women. Several predictions of this hypothesis are examined here by comparisons of parental ages among various populations. These revealed that: (1) mean maternal age of Down syndrome live births is slightly lower than that of Down syndrome spontaneous fetal deaths; (2) mean maternal age of those with mutant D/21 translocation Down syndrome is about the same as that of controls; (3) the ages of Down syndrome mothers who have Down syndrome live births is slightly lower than ages of Down syndrome mothers who have unaffected live births; and (4) in recent data on 47, +21 cases in which the extra chromosome 21 is of paternal origin, the mean maternal ages are 4-5 years lower than the maternal ages of cases of maternal origin (in contrast to earlier reports). All of these observations are contrary to the hypothesis that relaxed selection contributes significantly to the maternal-age association of Down syndrome. If there is any effect of relaxed selection, it is likely to be very weak and/or act primarily upon abortions that occur before recognition of pregnancy.     

Maternal cigarette smoking, Down syndrome in live births, and infant race.

Previous studies have suggested that maternal smoking is negatively associated with a Down syndrome live birth. We analyzed the data of the U.S. Perinatal Collaborative Study in a search for racial variation in Down syndrome risk factors. There were 22 cases in 25,346 live births to smoking mothers (4/10,780 blacks, 18/13,320 whites, and 0/1,246 other races) and 42/29,130 live births to nonsmoking mothers (24/14,665 blacks, 14/11,694 whites, and 4/2,771 others). The crude overall rates per 1,000 live births were 0.4 in black smokers and 1.6 in black nonsmokers but 1.4 in white smokers and 1.2 in white non-smokers. Adjusted for maternal age, the summary relative risk for a Down syndrome live birth to a smoking mother was 0.2 in blacks (95% interval 0.1-0.7) but 1.2 in whites (95% interval 0.6-2.5). Stratification on variables associated with socioeconomic status or gestational age at time of entry into the study did not alter the racial difference. A comparison of smokers with those who never smoked revealed essentially the same trends. Among all nonsmokers the ratio of the maternal age-adjusted risks for a Down syndrome live birth in whites compared with blacks was 0.7 (95% interval 0.3-1.3), and among all smokers this ratio was 3.6 (95% interval 1.3-9.9). If the results are not attributable to statistical fluctuation or undetected confounding, then differences in the probability of intrauterine survival of the Down syndrome fetus would appear to be one plausible explanation for the difference.     

Maternal BMI and country of birth as indicators of childhood obesity in children of Mexican origin

Objective: The goal of this study was to evaluate the relationship between maternal and childhood BMI at baseline in a group of 5‐ to 18‐year‐old children and their mothers, all of whom were of Mexican origin, low socioeconomic status, and enrolled in a cohort study in Houston, TX. Research Methods and Procedures: Using data from 438 mother‐child dyads residing in the same household, we completed logistic regression analyses to determine maternal factors associated with the child being overweight or at‐risk‐for‐overweight, after adjusting for the child's gender, age, and level of physical activity and other maternal confounders. Results: Almost one‐half of the boys and girls (47% and 44%, respectively) were either overweight or at‐risk‐for‐overweight. Obese mothers were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with normal‐weight mothers. Women born in the U.S. were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with women born in Mexico. In addition, women with less than a high school education were twice as likely to have an overweight child compared with their more educated peers. Discussion: The high prevalence of overweight or at‐risk‐for‐overweight among Mexican‐origin children of low socioeconomic status suggests a continued need to develop and implement culturally sensitive preventive interventions for this minority population. Our data also suggest a need to tailor such interventions particularly for children of obese mothers and those born in the U.S.     

Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects

We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than 20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.     

Independent effects of maternal age and birth order on the incidence of selected congenital malformations

Incidence rates, specific for maternal age and birth order, were calculated for 16 categories of congenital malformations reported on birth certificates from a population of more than 8 million registered, white, single livebirths. With maternal age held constant, none of the malformations showed increasing incidence as birth order increased. Hypospadias, esophageal defects, omphalocele, and Down syndrome showed evidence of decreasing incidence as birth order increased. Some of the other malformation categories showed an excess of 1st births in most age groups, while no relation to birth order was observed in the incidence of other malformations. By contrast, most of the malformations analyzed exhibited increasing incidence as maternal age increased. Especially high rates of several malformations were observed among 1st births to women over age 40.     

Sudden infant death syndrome and postneonatal mortality in immigrants in England and Wales.

To examine ethnic differences in postneonatal mortality and the incidence of sudden infant death in England and Wales during 1982-5 records were analysed, the mother''s country of birth being used to determine ethnic group. Postneonatal mortality was highest in infants of mothers born in Pakistan (6.4/1000 live births) followed by infants of mothers born in the Caribbean (4.5) and the United Kingdom and Republic of Ireland (4.1). Crude rates were lower in infants of mothers born in India (3.9/1000), east and west Africa (3.0), and Bangladesh (2.8) than in infants of mothers born in the United Kingdom despite less favourable birth weights. Mortality ratios standardised separately for maternal age, parity, and social class were significantly higher in infants of mothers born in Pakistan and lower in those of mothers born in Bangladesh. The ratio for infants of Caribbean mothers was significantly higher when adjusted for maternal age. Ratios for infants of Indian and east African mothers did not show significant differences after standardisation. An important finding was a low incidence of sudden infant death in infants of Asian origin. This was paralleled by lower mortality from respiratory causes. During 1975-85 postneonatal mortality in all immigrant groups except Pakistanis fell to a similar or lower rate than that in the United Kingdom group; Pakistanis showed a persistent excess. During 1984-5 several immigrant groups (from the Republic of Ireland, India, west Africa, and the Caribbean) recorded an increase in postneonatal mortality. Surveillance of postneonatal mortality among ethnic communities should be continued, and research is needed to identify the causes underlying the differences.     

Epidemiology of Down syndrome in South Australia, 1960-89.

During 1960-89 687 Down syndrome live births and 46 Down syndrome pregnancy terminations were identified in South Australia. Ascertainment was estimated to be virtually complete. The sex distribution of Down syndrome live births was found to be statistically different from the non-Down syndrome live-birth sex distribution (P less than .01). Smoothed maternal age-specific incidence was derived using both maternal age calculated to the nearest month and a discontinuous-slope regression model. The incidence of Down syndrome at birth for the study period was estimated to be 1.186 Down syndrome births/1,000 live births. Annual population incidence was shown to be correlated with trends in the maternal age distribution of confinements. If current trends in the maternal age distribution of confinements continue, the population incidence of Down syndrome in South Australia is predicted to exceed 1.5 Down syndrome births/1,000 live births during the 1990-94 quinquennium.     

南宁地区唐氏综合征患者的细胞遗传学研究

为了探讨中国南宁地区唐氏综合征患者染色体核型分布及其特点, 对广西壮族自治区妇幼保健院1994年以来的500例疑似唐氏综合征(Down syndrome, DS)患者进行外周血染色体核型分析, 130例确诊为DS患者。其中, 单纯型21-三体为86.15%(112/130); 易位型为8.46%(11/130); 嵌合型为5.39%(7/130)。在单纯型21-三体中性别比为女∶男=1∶1.8; 93.08% 的唐氏综合征患儿由年轻母亲(<35岁)所生, 另有6.92% 由高龄产妇所生。结果表明, 南宁地区86% 以上唐氏综合征患者的染色体核型是单纯型21-三体, 男性唐氏综合征患儿明显高于女性患儿。     

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.     

Cigarette smoking and Down syndrome.

A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the normal controls but not for the defect controls. The risk ratios for the association of cigarette smoking around the time of conception with Down syndrome was 0.58 (90% confidence interval of 0.34-0.98) in the case-defect control comparison and 0.56 (90% confidence interval of 0.33-0.95) in the case-normal control comparison. Stratification by alcohol ingestion and maternal age did not abolish the negative trend to association. The results are contrary to that of an earlier study of others that found a positive association of older age and trisomy in spontaneous abortions. In fact, among mothers of Down syndrome cases over age 30 in this analysis, the risk ratio was lower than for younger mothers. (For case-normal control comparisons, the value was 0.39 [90% confidence interval of 0.17-0.87]). If not due to chance or confounding, the negative association in our data may be attributable to, among other factors, a selective effect of smoking upon survival or fertilizability of +21 gametes prior to conception or upon survival of +21 conceptuses after fertilization.     

Maternal severe migraine and risk of congenital limb deficiencies

BACKGROUND: Migraines occurs frequently during pregnancy; however, there are no published data on their possible teratogenic potential in a controlled epidemiological study. Therefore, we examined the risk of congenital abnormalities in infants born to women who had migraines and other headaches during pregnancy. METHODS: Between 1980 and 1996, the Hungarian Case-Control Surveillance of Congenital Abnormalities evaluated 22,843 cases (newborns or fetuses) with congenital abnormalities, 38,151 control newborn infants without any abnormalities, and 834 malformed controls with Down syndrome. RESULTS: Migraines anytime during pregnancy occurred in 565 (2.5%) mothers of the case group compared with 713 (1.9%) mothers in the control group (crude prevalence odds ratio [POR], 1.3; 95% confidence interval [CI], 1.2-1.5) and 24 (2.9%) pregnant women in the malformed control group (crude POR, 0.9; 95% CI, 0.6-1.3) The mothers of 247 cases, 533 controls, and 21 malformed controls had severe migraines during the second and/or third months of pregnancy. There was only 1 congenital abnormality group: limb deficiencies, which had a higher rate of maternal migraines during the second and third months of pregnancy both at the comparison of cases and matched controls (adjusted POR, 2.5; 95% CI, 1.1-5.8) and of cases and malformed controls (adjusted POR, 1.7; 95% CI, 1.3-3.0). There was no association between other headaches and different congenital abnormalities at the comparison of cases and controls. CONCLUSIONS: Our data showed that maternal severe migraines during the second and/or third months of pregnancy were associated with an increased risk of congenital limb deficiencies. A similar association was not detected between congenital anomalies and other headaches during pregnancy. Our study was not based on a prior hypothesis; therefore, these data can be considered only as a signal that needs confirmation by independent data sets.     

Size at birth,maternal nutritional status in pregnancy,and blood pressure at age 17: population based analysis.

OBJECTIVE: To assess the effect of size at birth, maternal nutrition, and body mass index on blood pressure in late adolescence. DESIGN: Population based analysis of birth weight corrected for gestational age, mother''s weight before pregnancy and weight gain in pregnancy, obtained from the Jerusalem perinatal study, and blood pressure and body mass index at age 17, available from military draft records. SETTING: Jerusalem, Israel. SUBJECTS: 10,883 subjects (6684 men and 4199 women) born in Jerusalem during 1974-6 and subsequently drafted to the army. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures measured at age 17 and their correlation with birth weight, size at birth, mother''s body mass index and weight gain during pregnancy, and height and weight at age 17. RESULTS: Systolic and diastolic blood pressures were significantly and positively correlated with body weight, height, body mass index at age 17, and with mother''s body weight and body mass index before pregnancy, but not with birth weight or mother''s weight gain in pregnancy. CONCLUSION: Variables reflecting poor intrauterine nutrition, including low maternal body mass index before pregnancy, poor maternal weight gain in pregnancy, and being born small for gestational age, were not associated with a higher blood pressure in late adolescence.     

Maternal fever and neural tube defects

It has been proposed that hyperthermia in the pregnant woman is associated with neural tube defects in her offspring. We analyzed retrospective interview data for a maternal history of probable febrile illness during the first trimester of pregnancy among mothers of infants with anencephaly or spina bifida. There were two control groups--mothers of infants with Down syndrome and mothers of infants with cleft lip or palate. With the Down syndrome group serving as controls, the incidence of febrile illness among mothers of all infants with neural tube defects was significantly elevated. With the cleft group as controls, the fever incidence was not significantly increased in the neural tube defect groups. When the combined cleft and Down syndrome controls were used, only mothers of the spina bifida group had an elevated fever incidence. Epidemiology data suggest an association of maternal fever during pregnancy with neural tube defects in the offspring.     

Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.     

Mitochondrial analysis sheds light on the origin of hair sheep

A total of 180 mtDNA sequences from hair Caribbean (93), West African (73) and Canarian‐wooled (14) sheep were analysed to shed light on the origin of hair sheep. A comparison of 360 Iberian sheep sequences retrieved from GenBank was performed to assess a possible European origin of the Caribbean hair sheep. These 180 sequences gave 48 different haplotypes (16 in Caribbean sheep). All Caribbean and Canarian‐wooled sequences and 91.8% of the West African samples belonged to haplogroup B. The sheep analysed showed wide haplotypic identity. Caribbean sheep shared roughly two‐thirds of their samples with Canarian‐wooled and West African samples, respectively. Principal component analysis showed that the Caribbean and the Canarian‐wooled sheep clustered together. Additional analyses showed that hair and Iberian sheep had wide genetic identity. It was not possible to ascertain a single Canarian, African or European origin of the Caribbean hair sheep using mtDNA markers only. European, African and Caribbean hair sheep maternal genetic backgrounds likely result from related domestication events.