Trisomy 18 in neonates: prenatal diagnosis, clinical features, therapeutic dilemmas and outcome

The study aimed to analyse the clinical courses of aggressively treated neonates with cytogenetically confirmed trisomy 18, with special attention focused on the efficiency of prenatal diagnostics, associated malformations, therapeutic dilemmas and outcomes. We investigated retrospectively the data concerning 20 neonates with trisomy 18, admitted to the Neonatal Intensive Care Unit (NICU) in Katowice between January 2000 and February 2005. Their birth weights ranged from 650 g to 2400 g, mean 1812 g; gestational age ranged from 27 to 42 weeks, median 38 weeks. Intrauterine growth retardation was noticed in 90% of neonates. Trisomy 18 was suspected prenatally in 40% of cases. Most (80%) of newborns were delivered by caesarean section (92% of neonates with prenatally unrecognized chromosomal defects, 62% of neonates with trisomy 18 suspicion) and 70% of infants needed respiratory support immediately after birth. Cardiac defects were present in 95%, central nervous system malformations in 65%, severe anomalies of digestive system or abdominal wall in 25% of patients. Nine surgical operations were performed during hospitalization (4 were palliative cardiac surgeries). Six patients (30%) survived the neonatal period and were discharged from the NICU. The median survival of the neonates who died was 20 days. In 4 cases cardiac problems implicated their death; in others, deaths were attributed to multiorgan failure, prematurity and/or infection. Further improvement of efficiency of prenatal ultrasound screening for diagnosis of trisomy 18 in the fetus is necessary. A lack of prenatal diagnosis of trisomy 18 in the fetus results in a high rate of unnecessary caesarean sections in these pregnancies. Despite the aggressive treatment most neonates with trisomy 18 died during the neonatal period. The majority of deaths were attributed to cardiorespiratory and multiorgan failure. Concerning the poor prognosis, prompt karyotyping (using FISH) of clinically suspected trisomy 18 is very important, because many invasive procedures and surgeries may then be avoided.     

Better Prognosis in Newborns with Trisomy 13 Who Received Intensive Treatments: A Retrospective Study of 16 Patients

Intensive treatment for newborns with trisomy 13 is controversial because of their lethal prognosis. We report the better life prognosis of patients with trisomy 13 who received intensive treatment. At our hospital, we provided an intensive management to such patients including resuscitation and surgical procedures as required. Herein, we present the results of a retrospective study (1989-2010) of 16 trisomy 13 cases who received an intensive treatment. None was diagnosed to have trisomy 13 before birth; 9 were delivered by C-section and oxygen was administered to all patients during postpartum resuscitation. Mechanical ventilation was used in 9 patients after tracheal intubation and tracheotomy was performed in 2 patients when withdrawing of extubation was difficult. Regarding prognosis, 9 patients died, 3 were referred to another hospital, and 4 were discharged from the hospital. Four and 7 patients died within 7 and 30 days after birth, respectively. Nine patients survived for >1 month, 7 for >180 days, and 5 for >3 years. Median survival for 16 patients was 733 days. The patients who received intensive treatments survived longer compared to the previous data. This study provides useful information concerning genetic counseling, especially from an ethical point of view, before providing intensive management to newborns with trisomy 13.     

Current status of chromosomal abnormalities in mouse embryonic stem cell lines used in Japan

We performed chromosomal analysis on 540 mouse embryonic stem (ES) cell lines obtained during 2001 to 2004 from 20 institutions in Japan. Overall, 66.5% of the ES cell lines showed normal chromosomal numbers, but 15.9%, 9.1%, and 2.8% showed modal chromosomal numbers of 41, 42, and 39, respectively. When we karyotyped 88 ES cell lines selected arbitrarily from the 540 lines, 53 (60.2%) showed normal diploid karyotypes; the sex chromosome constitution of 52 lines was XY, with the remaining 1 being XX. Among 35 ES cell lines showing abnormal karyotypes, trisomy of chromosome 8 (41, XY, +8) was dominant (51.4%), 14.3% had trisomy 8 with loss of one sex chromosome (40, XO, +8), and 11.4% had trisomy 8 together with trisomy 11 (42, XY, +8, +11). Karyotypic abnormalities including trisomy 8 and trisomy 11 occurred in 88.6% and 17.1% of ES cell lines, respectively. The XO sex chromosome constitution was observed in 25.7% of all abnormal ES cell lines. Of the 88 selected ES cell lines, 60 lines were established from strain 129 animals, 17 from F1 progeny of C57BL/6J x CBA (called TT2 in this study), and 11 from C57BL/6J mice. Normal diploid karyotypes were observed in 58.3% of lines derived from 129, 58.8% of those from TT2, and 72.7% of C57BL/6J. The relatively high incidence of abnormalities in chromosomal number and karyotype in ES cell lines used in Japan suggests the importance of chromosomal analysis of ES cells for successful establishment of new animal models through germline transmission.     

Trisomies 13 and 18: prenatal diagnosis and epidemiologic studies in Hawaii, 1986-1997

Using a birth defects registry, this study examined the influence of prenatal diagnosis and elective termination of pregnancy on trisomy 13 and trisomy 18 prevalence in Hawaii between 1986 and 1997. The investigation also evaluated the impact of various demographic factors on risk for the aneuploidies. Forty-seven cases of trisomy 13 and 116 cases of trisomy 18 were identified. The total prevalence of trisomy 13 was 1.91 per 10,000 births and of trisomy 18 was 4.71 per 10,000 births. Elective terminations accounted for 38.3% of trisomy 13 cases and 48.3% of trisomy 13 cases. The 1-year mortality rate for trisomy 13 was 89.5% and for trisomy 18 was 74.3%. Rates for both aneuploidies increased during the time period. The racial/ethnic group with the highest prevalence of both anomalies was Far East Asian. The aneuploidies were more common in metropolitan Honolulu than the rest of Hawaii. Demographic factors demonstrated differences in risk for trisomies 13 and 18, although most of these differences appeared to be due, at least in part, to differences in maternal age distribution. For the secular trend, increased prenatal diagnosis of the anomalies also contributed to the observed increase.     

Double trisomy in spontaneous abortions

Cytogenetic data on products of conception from spontaneous abortions studied over a 10-year period have been reviewed for double trisomies. A total of 3034 spontaneous abortions were karyotyped between 1986 and 1997. Twenty-two cases with double trisomy, one case with triple trisomy, and a case with a trisomy and monosomy were found. The tissues studied were mostly sac, villi, or placenta. The gestational age ranged from 6 to 11 weeks and the mean age was 8.2 ± 1.7 (SD) weeks. The mean maternal age in years was 35.9 ± 5.3. Of the twenty-two cases, four were mosaics. All but two of the cases involved autosomal aneuploidies. The double trisomies included chromosomes 2, 4, 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 20, 21, and 22. The chromosomes that were trisomic in more than one double trisomy case were numbers 16 (8 cases), 8 (5 cases), 15 (4 cases), 2, 13, and 21 (3 cases each), and 5, 7, 14, 18, 20, 22, and X (2 cases). The triple trisomy involved chromosomes 18, 21, and X. The monosomy and trisomy case was a mosaic, with a monosomy 21 in all cells and some cells also with a trisomy 5. The double trisomies cited for the first time in this study were 4/13, 5/16, 8/14, 8/15, 14/21, 15/20, and 7/12. The pooled mean maternal age for double trisomy cases (34.1 ± 5.7 years) was higher than that for single trisomy cases (31 ± 6.1 years). The difference was statistically significant at P = < 0.001. The pooled mean gestational age of spontaneous abortions was lower for double trisomy (8.7 ± 2.2 weeks) than for reported single trisomy cases (10.1 ± 2.9 weeks). This difference is also statistically significant at P = < 0.001. The sex ratio among double trisomies was 15 females to 13 males. This difference was not statistically significant from the expected 1 : 1. Received: 27 June 1997 / Accepted: 4 September 1997     

Trisomy 11p15 and Beckwith-Wiedemann syndrome. Report of two new cases

An association between trisomy 11p15 and Beckwith-Wiedemann syndrome is described in two brothers. The first presented at birth with gigantism and macroglossia, umbilical hernia and abdominal distention, hypoglycemia and atresia of the pulmonary artery, leading to the diagnosis of Beckwith-Wiedemann syndrome. Facial dysmorphism also included: a hypoplastic midface, hypertelorism, and a short nose with a flattened bridge. The karyotype showed a trisomy 11p15 with a monosomy 18p11, due to a t(11;18)(p154;p111)pat. His brother, born a year later, showed the same signs. The association between trisomy 11p15 and Beckwith-Wiedemann syndrome is in certain cases well established.     

Effect of cell confluence on production of cloned mice using an inbred embryonic stem cell line

Mice have been successfully cloned from both somatic cells and hybrid embryonic stem (ES) cells. Heterozygosity of the donor ES cell genome has been suggested as a crucial factor for long-term survival of cloned mice. In the present study, an inbred ES cell line, HM-1 (129/Ola), and a well-tested ES cell line, R1 (129/Sv x 129/Sv-CP), were used as donor cells to evaluate the developmental potential of nuclear transfer embryos. We found that ES cell confluence dramatically affects the developmental potential of reconstructed embryos. With the ES cell line HM-1 and 80-90% confluence, 49% of reconstructed embryos developed to the morula/blastocyst stage, 9% of these embryos developed to live pups when transferred to the surrogate mothers, and 5 of 18 live pups survived to adulthood. By contrast, at 60-70% confluence, only 22% of embryos developed to the morula/blastocyst stage, and after transfer, only a single fetus reached term. Consistent with previous reports, the nuclei of R1 ES cells were also shown to direct development to term, but no live pups were derived from cells at later passages (>20). Our results show that the developmental potential of reconstructed embryos is determined by both cell confluence and cell passage. These results also demonstrate that the inbred ES cell line, HM-1, can be used to produce viable cloned mice, although less efficiently than most heterozygous ES cell lines.     

Kin and birth order effects on male child mortality: three East Asian populations, 1716–1945

Human child survival depends on adult investment, typically from parents. However, in spite of recent research advances on kin influence and birth order effects on human infant and child mortality, studies that directly examine the interaction of kin context and birth order on sibling differences in child mortality are still rare. Our study supplements this literature with new findings from large-scale individual-level panel data for three East Asian historical populations from northeast China (1789–1909), northeast Japan (1716–1870), and north Taiwan (1906–1945), where preference for sons and first-borns is common. We examine and compare male child mortality risks by presence/absence of co-resident parents, grandparents, and other kin, as well as their interaction effects with birth order. We apply discrete-time event-history analysis on over 172,000 observations of 69,125 boys aged 1–9 years old. We find that in all three populations, while the presence of parents is important for child survival, it is more beneficial to first/early-borns than to later-borns. Effects of other co-resident kin are however null or inconsistent between populations. Our findings underscore the importance of birth order in understanding how differential parental investment may produce child survival differentials between siblings.     

Patterns of first-year survival among infants with selected congenital anomalies in Texas, 1995-1997.

BACKGROUND: Few registry-based studies have investigated survival among infants with congenital anomalies. We conducted a registry-based study to examine patterns and probability of survival during the first year of life among infants with selected congenital anomalies. METHODS: Data from the Texas Birth Defects Monitoring Division were merged with linked birth-infant death files for 2,774 infants born January 1, 1995 to December 31, 1997, with at least 1 of 23 common anomalies. Deaths before the first birthday were assessed from infant death files. Kaplan-Meier was used to estimate first-year survival; first-year survival was assessed for specific anomalies and by the number of life-threatening anomalies. RESULTS: Overall, 80.8% of infants with these 23 anomalies survived the first year of life. We observed the highest survival rates for infants with gastroschisis (92.9%, 95% CI = 86.8, 96.3), trisomy 21 (92.3%, 95% CI = 89.5, 94.4) or cleft lip with or without cleft palate (87.6%, 95% CI = 84.0, 90.5). Infants with intermediate survival rates included those with microcephaly (79.7%; 95% CI = 73.6, 84.6), tetralogy of Fallot (75.0%; 95% CI = 65.5, 82.2), or with diaphragmatic hernia (72.8%; 95% CI = 61.8, 81.2). As expected, all infants with anencephaly and almost all infants with trisomy 13 or trisomy 18 died during the first year of life. First-year survival declined as the number of co-occurring life-threatening anomalies increased. CONCLUSIONS: Overall, first-year survival for infants with congenital anomalies was high. Additional population-based studies are needed to quantify improvements in first-year survival.     

Molecular studies of chromosomal mosaicism: relative frequency of chromosome gain or loss and possible role of cell selection.

Studies of uniparental disomy and origin of nonmosaic trisomies indicate that both gain and loss of a chromosome can occur after fertilization. It is therefore of interest to determine both the relative frequency with which gain or loss can contribute to chromosomal mosaicism and whether these frequencies are influenced by selective factors. Thirty-two mosaic cases were examined with molecular markers, to try to determine which was the primary and which was the secondary cell line: 16 cases of disomy/trisomy mosaicism (5 trisomy 8, 2 trisomy 13, 1 trisomy 18, 4 trisomy 21, and 4 involving the X chromosome), 14 cases of 45,X/46,XX, and 2 cases of 45,X/47,XXX. Of the 14 cases of mosaic 45,X/46,XX, chromosome loss from a normal disomic fertilization predominated, supporting the hypothesis that 45,X might be compatible with survival only when the 45,X cell line arises relatively late in development. Most cases of disomy/trisomy mosaicism involving chromosomes 13, 18, 21, and X were also frequently associated with somatic loss of one (or more) chromosome, in these cases from a trisomic fertilization. By contrast, four of the five trisomy 8 cases were consistent with a somatic gain of a chromosome 8 during development from a normal zygote. It is possible that survival of trisomy 8 is also much more likely when the aneuploid cell line arises relatively late in development.     

The protective effects of monoclonal antibodies in mice from Naegleria fowleri infection]

Protective effects of monoclonal antibodies against N. fowleri were comparatively studied. BALB/c mice were treated with two types of monoclonal antibodies, Nf 2 and Nf 154, before and after the infection with N. fowleri. The mortality and mean survival times were then compared. Also, direct effect of the monoclonal antibodies on the N. fowleri trophozoites in vitro were observed. In vitro protective effects of the monoclonal antibodies were also studied in cells infected with N. fowleri. The observed results are summarized as follows: 1. Among mice pretreated twice before the infection with monoclonal antibody Nf 2(McAb Nf 2), only 15.8% were killed, and the mean survival time was 17.7 days. This was not much different from the mice pretreated once, as the mortality and mean survival time were 16.7% and 17 days. Those effects were compatible with monoclonal antibody Nf 154(McAb Nf 154). The above findings contrast with the mortality and mean survival time of the control mice, which were 22.7% and 14.6 days respectively. 2. Mice which received twice the McAb Nf 2 following N. fowleri infection incurred a 19.4% mortality rate with 13.6 days survival time; 17.9% and 15.8 days with on time administration, in contrast to the 25% and 14.6 days in the control group. 3. Marked agglutination effect of McAb Nf 2 or McAb Nf 154 were observed on N. fowleri trophozoites. 4. When N. fowleri trophozoites were treated with McAb Nf 2 or McAb Nf 154 combined with comments, the proliferation rate was more significantly suppressed than in that the control. 5. N. fowleri trophozoites treated with McAb Nf 2 or McAb Nf 154 showed an increased number of swollen mitochondria, disfigured cisternae, lipid droplets, and osmiophilic granules in the cytoplasm. 6. A remarkable protective effect of monoclonal antibodies was noticed in CHO cells infected with N. fowleri. More than 90.6% of the infected CHO cells survived, contrasted with 27% of untreated cells. The overall results in this study suggest that N. fowleri treated with monoclonal antibodies against N. fowleri reduce the mortality and prolong the survival time of the mice when the antibodies are administered before the infection. The protective effect of the monoclonal antibodies is surmised being caused by agglutination of the trophozoites.     

Trisomy recurrence: a reconsideration based on North American data

Few reliable data exist concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome. We collected records from two sources: (1) prenatal diagnoses performed at the Hopital Sainte-Justine in Montreal and (2) karyotype analyses performed at Genzyme. Using the standardized morbidity ratio (SMR), we compared the observed number of trisomies at prenatal diagnosis with the expected numbers, given maternal age-specific rates (by single year). SMRs were calculated both for recurrence of the same trisomy (homotrisomy) and of a different trisomy (heterotrisomy). After all cases with an index trisomy 21 were combined, the SMR for homotrisomy was 2.4 (90% CI 1.6-3.4; P=.0005). For women with both the index trisomy and subsequent prenatal diagnosis at age <30 years, the SMR was 8.0; it was 2.1 for women with both pregnancies at age >/=30 years. For the other index viable trisomies (13, 18, XXX, and XXY) combined, the SMR for homotrisomy was 2.5 (90% CI 0.7-8.0). For heterotrisomy, the SMR after an index trisomy 21 was 2.3 (90% CI 1.5-3.8, P=.0007); the SMR did not vary with maternal age at the first trisomy. When all cases with index viable trisomies were combined, the SMR for heterotrisomy was 1.6 (90% CI 1.1-2.4; P=.04). For prenatal diagnoses following a nonviable trisomy diagnosed in a spontaneous abortion (from Genzyme data only), the SMR for a viable trisomy was 1.8 (90% CI 1.1-3.0; P=.04). The significantly increased risk for heterotrisomy supports the hypothesis that some women have a risk for nondisjunction higher than do others of the same age.     

Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing

Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable.     

Age of first breeding and incidence of dystocia and losses at parturition and post-partum in the indigenous Nigerian pig

Studies were carried out on the prevalence of dystocia and losses at parturition and post-partum following early mating and first breeding in 15 Nigerian indigenous pigs. Six were 8 months old at the time of their first farrowing, while nine were 11 or 12 months at the time of their first farrowing. Forty-six piglets were born, of which 11 died at birth (24%) and a further 18 during the next 7 days (total loss 63.0%). The six pigs that farrowed at 8 months of age had smaller mean litters and birth weights, a higher incidence of dystocia and higher piglet mortality at birth than those that farrowed later (32 with 91% survival). However, increased age at first farrowing did not reduce the high death rate during the first week (50% of piglets which survived at birth in both groups). This was attributed to starvation due to poor mothering ability following first farrowing since there was no agalactia or mastitis.     

Prenatal diagnosis of trisomy 21: registration results from a single genetic center

This is a retrospective review of all collected amniotic fluid samples, chorionic villus samples and other fluid-aspirations (hygroma colli fluid/urine from megacystis) over an 11-year period (1996-2006) in a single Genetic Center (University Hospital Gasthuisberg, Leuven), looking at the prenatal diagnosis of trisomy 21. In this study a total of 404 diagnoses of trisomy 21 were made on 29696 samples (1.4%). The prenatal diagnosis of trisomy 21 increased over the years with 0.88% (21/2363) in 1996 and 1.99% (50/2512)in 2006. Also the type of invasive testing changed over the years with an increase of the proportion of trisomy 21- diagnoses by chorionic villussampling from 2001. Looking at the registry for perinatal activities in Flanders for the year 2006 the live birth incidence for trisomy 21 was 1/1782 and this is lower than the often reported incidence oftrisomy 21 at birth of 1/800: it is likely that the use of more sensitive screening methods for the prenatal detection of trisomy 21 and the election of termination for most affected pregnancies affects the birth incidence oftrisomy 21.     

Interchange trisomy 21 by t(1;21)(p22;q22)mat

Interchange trisomy 21 by t(1:21)(p22:q22)mat: Interchange trisomy 21 by t(1;21)(p22;q22)mat was identified in a sporadic patient with Down syndrome. With a 21q22 specific probe, we observed signals on both normal 21 chromosomes and on the der. We reviewed the 23 published reports of families with reciprocal translocations leading to viable offspring with interchange trisomy 21. The breakpoints in chromosome 21 were mainly located in 21q (19/24 instances, including the present report) and in 19/23 cases the other chromosome involved in the translocation was (pairs 1-12). The underlying 3:1 segregation occurred mainly in carrier mothers; only one patient presented a de novo imbalance and in another case the father was the carrier. In addition, there were 4 instances of concurrence with another unbalanced segregation (adjacent-1 or tertiary trisomy) and 3 families with recurrence of interchange trisomy 21. The mean age of 14 female carriers at birth of interchange trisomy 21 offspring (24.8 yr) was lower that the mean (28.3 yr) found in a larger sample of mothers of unbalanced offspring due to 3:1 segregation (mostly tertiary trisomics) and was not increased with respect to the general population average. Overall, these data agree with previous estimates regarding recurrence risk (9-15%) and abortion rate (about 28%) in female carriers ascertained through an interchange trisomic 21 child.     

Late deaths and survival after childhood cancer: implications for cure.

OBJECTIVES--To investigate causes of death and survival in subjects who had survived at least five years after diagnosis of childhood cancer; to compare observed mortality with that expected in the general population; and to compare results with a corresponding cohort diagnosed earlier. DESIGN--Retrospective cohort study. SETTING--Population based National Register of Childhood Tumours. SUBJECTS--9080 five year survivors of childhood cancer diagnosed in Britain during 1971-85, of whom 793 had died. Comparison with corresponding cohort diagnosed during 1940-70. MAIN OUTCOME MEASURES--Cause of death established from all available sources of information (including hospital and general practitioner records and postmortem reports) and underlying cause of death coded on death certificate. RESULTS--Of the 781 deaths for which sufficient information was available, death was attributed to recurrent tumour in 578 (74%) cases, treatment related effect in 121 (15%), second primary tumour in 52 (7%), and other causes in 30 (4%). Comparison of observed mortality with that expected in the general population indicated a fourfold excess of deaths from non-neoplastic causes. The risk of dying of recurrent tumour in the next 10 years after surviving five years from diagnosis during 1940-70 and 1971-85 fell from 12% to 8%. The risk of dying from a treatment related effect increased slightly from 1% to 2%. CONCLUSION--Improvements in five year survival after childhood cancer have been accompanied by a reduction in risk of dying from recurrent tumour during the subsequent 10 years and by a slight increase in risk of dying from treatment related effects. The results provide information relevant to decisions concerning balance between effective treatments and their potentially harmful effects.     

False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review

Non-invasive prenatal testing (NIPT) demonstrated a small chance for a false negative result. Since the “fetal” DNA in maternal blood originates from the cytotrophoblast of chorionic villi (CV), some false negative results will have a biological origin. Based on our experience with cytogenetic studies of CV, we tried to estimate this risk. 5967 CV samples of pregnancies at high risk for common aneuplodies were cytogenetically investigated in our centre between January 2000 and December 2011. All cases of fetal trisomy 13, 18 and 21 were retrospectively studied for the presence of a normal karyotype or mosaicism < 30% in short-term cultured (STC-) villi. 404 cases of trisomies 13, 18 and 21 were found amongst 5967 samples (6,8%). Of these 404 cases, 14 (3,7%) had a normal or low mosaic karyotype in STC-villi and therefore would potentially be missed with NIPT. It involved 2% (5/242) of all trisomy 21 cases and 7.3% (9/123) of all trisomy 18 cases. In 1:426 (14/5967) NIPT samples of patients at high risk for common aneuploidies, a trisomy 18 or 21 will potentially be missed due to the biological phenomenon of absence of the chromosome aberration in the cytotrophoblast.     

Maternal Folate Polymorphisms and the Etiology of Human Nondisjunction

Attempts to identify genetic contributors to human meiotic nondisjunction have met with little, if any, success. Thus, recent reports linking Down syndrome to maternal polymorphisms at either of two folate metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), have generated considerable interest. In the present report, we asked whether variation at MTHFR (677C-->T) or MTRR (66A-->G) might be associated with human trisomies other than trisomy 21. We analyzed maternal polymorphisms at MTHFR and MTRR in 93 cases of sex-chromosome trisomy, 44 cases of trisomy 18, and 158 cases of autosomal trisomies 2, 7, 10, 13, 14, 15, 16, 18, or 22, and compared the distributions of genotypes to those of control populations. We observed a significant increase in the MTHFR polymorphism in mothers of trisomy 18 conceptuses but were unable to identify any other significant associations. Overall, our observations suggest that, at least for the sex chromosomes and for a combined set of autosomal trisomies, polymorphisms in the folate pathway are not a significant contributor to human meiotic nondisjunction.