Non-mosaic Trisomy Research Articles

Non-Mosaic Trisomy 7 in Chorionic Villi and Trisomy 18 in the Fetus: An Extreme form of Mosaic Variegated Aneuploidy?

Non-Mosaic Trisomy 7 in Chorionic Villi and Trisomy 18 in the Fetus: An Extreme form of Mosaic Variegated Aneuploidy?

Non-Mosaic Trisomy 7 in Chorionic Villi and Trisomy 18 in the Fetus: An Extreme form of Mosaic Variegated Aneuploidy?

Non-Mosaic Trisomy 7 in Chorionic Villi and Trisomy 18 in the Fetus: An Extreme form of Mosaic Variegated Aneuploidy?

Monozygotic twins discordant for trisomy 21 and maternal 21q inheritance: A complex series of events

We report on a monochorionic/diamniotic twin pregnancy discordant for trisomy 21. Amniocentesis (at 13(5/7) weeks) was performed following ultrasound signs of hydrops and cystic hygroma in twin 1 (T1). Prenatal karyotype showed non-mosaic trisomy 21 in T1 (47,XX,+21[7]), and low-grade mosaic trisomy 21 in twin 2 (T2) (47,XX,+21[2]/46,XX[19]). Post mortem examination of fetal skin, kidneys and lungs confirmed trisomy 21 in T1 (47,XX,+21[548]) and the placenta (47,XX,+21[200]). T2 had a normal karyotype (46,XX[648]). Analysis of microsatellite polymorphisms in multiple samples from the placenta, hand, lungs, kidneys and the umbilical cords of both twins confirmed monozygosity for all loci tested, and trisomy 21 in T1. Unexpectedly, T1 and T2 inherited different maternal alleles for markers of the most distal 4 Mbp of 21q. At least four successive events are needed to explain the genetic status of both twins and include maternal MI premature chromatids separation or maternal II meiotic nondisjunction and post-zygotic events such as, chromosome rescue, nondisjunction, an/or recombination.

Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism

Patau syndrome (trisomy 13) is very rare in live-born babies. Individuals with this chromosomal syndrome have a short lifespan and are rarely seen beyond infancy. This study is aimed at the clinical spectrum, natural history, and survival of patients with trisomy 13. We reviewed the detailed data of 13 Patau syndrome live-born babies. Among them two individuals were delivered from continuation of pregnancy even after prenatal diagnosis. The remaining 11 patients were born to younger mothers who did not undergo amniocentesis because no major anomalies except for cleft lip/palate were found on prenatal sonograms. The common features of Patau syndrome including the clinical triad (microphthalmia, cleft lip/palate, and polydactyly) and non-cyanotic heart defects were always found in our series. However, certain serious central defects (holoprosencephaly, omphalocele, and single umbilical artery), which are easily recognized from prenatal sonogram, occurred less frequently than those stated in the literature. The median survival time was 95 days and was longer than that previously reported. There were two infants with trisomic mosaicism with different outcomes in both clinical spectrum and survival. Otherwise, we also found the increased recurrence risks of aneuploidy in two individuals, and the longest survivor (84 months) of non-mosaic trisomy 13 in Taiwan. We thus suggest that long-term survival in our series is strongly correlated with different expressivity after prenatal selection, in addition to cytogenetic mosaicism. Less associated anomalies such as polyhydramnios, oligohydramnios, intrauterine growth retardation, single umbilical artery, eye defects, holoprosencephaly, omphalocele, and polycystic kidney may contribute to their clinical courses.

Fertility in men with Down syndrome: a case report

To inform clinicians about fertility in males with Down syndrome. Case report. Medical Genetics Department of a tertiary-care hospital. A 26-year-old man with confirmed nonmosaic trisomy 21. Karyotype, amniocentesis, paternity testing using microsatellite markers. Confirmed paternity in the son of a male with nonmosaic trisomy 21. A male with nonmosaic Down syndrome fathered a normal son, and the paternity was proven by microsatellite marker analysis. Although Down syndrome males have been reported to be infertile, it may not always be true. Infertility in males has been attributed to defective spermatogenesis, but ignorance of the sexual act may be one of the contributing factors. It is important to advise postpubertal Down syndrome males on contraceptive measures.

Non‐mosaic trisomy 22: a report of 2 cases

Non-mosaic trisomy 22 is a common cause of first trimester miscarriage and has a livebirth incidence of 1 in 30,000-50,000. Consequently there is a paucity of information for counselling parents. Detection in the second trimester is rare. It is commonly associated with severe growth retardation and multiple structural abnormalities. Oligohydramnios is frequently seen and can make detection of other abnormalities difficult. The outlook is uniformly poor and survival beyond the first trimester may present management dilemmas. A thorough fetal assessment including high-resolution cytogenetics with or without FISH is required for counselling. Careful plans for intrapartum and neonatal management may be necessary. The recurrence risk is thought to be low but information is very limited as there have been no reported cases of recurrence. We present two case of non-mosaic trisomy 22 including the first to be diagnosed subsequent to investigation for a high serum screening Down's risk.

Male pseudohermaphroditism and gonadal mosaicism in a 47,XY,+22 fetus

Trisomy 22 syndrome manifestations include cranial and facial anomalies. Ambiguous genitalia have been described in some fetus, but histological examination of the gonads has been rarely provided. We report here the first case of a male pseudohermaphrodite fetus with non-mosaic full trisomy 22 in amniocytes and presenting with ambiguous external genitalia, testes, and a uterus. In this case, we have further analyzed cytogenetically gonadal and uterine tissues. FISH analyses on paraffin-embedded gonads and uterus indicated the presence of two cell lines: XY and monosomy X, with 22%-50% of uterine cells having monosomy X, while 85%-100% of right and 77%-96% of left testicular cells were XY. The distribution of sex chromosomes observed in these tissues could explain the sexual differentiation observed in this fetus. On the other hand, this phenotype could also have resulted from cryptic anomalies in one or several genes implicated in sexual differentiation. Further evidence is thus needed before identifying the true cause of pseudohermaphroditism in our patient.

Rapid Prenatal Diagnosis of Aneuploidy Using Quantitative Fluorescence-PCR (QF-PCR)

Molecular cytogenetic aneuploidy testing for pregnant women at increased risk of chromosome abnormality leads to rapid reassurance for those with normal results and earlier decisions on pregnancy management in the case of abnormality. We tested 9080 prenatal samples using a one-tube QF-PCR test for trisomies 13, 18, and 21; the abnormality rate was 5.9%. There were no misdiagnoses for non-mosaic trisomy. A sex chromosome multiplex was developed that detects structural sex chromosome abnormalities as well as aneuploidies. The sex chromosome test was targeted at pregnancies (272) with specific abnormalities suggestive of Turner syndrome; 13.2% showed 45,X, confirmed by follow-up analysis.

Strategies for the rapid prenatal diagnosis of chromosome aneuploidy.

Rapid diagnosis of common chromosome aneuploidies in raised risk pregnancies, usually prior to full karyotype analysis, is now carried out in a number of European genetic centres; several techniques for detecting genomic copy number changes have been described. Prenatal diagnosis of genetic disease requires accurate and robust assays; the invasive procedures are associated with a risk of pregnancy loss and an abnormal result may lead to termination of the pregnancy. The testing of prenatal material (amniotic fluid, chorionic villi or, more rarely, fetal blood) is associated with specific problems, including the quality and quantity of the tissue and difficulties of interpretation due to phenomena such as maternal cell contamination and mosaicism. In addition, there are 24-h, high-throughput demands on centres offering such a service. The extent to which existing and proposed strategies, including different PCR-based assays, a multiplex ligation-dependent probe amplification approach, and microarrays, fulfil the requirements of rapid prenatal testing is discussed. In the past 3 years, we have tested 7720 prenatal samples for trisomies 13, 18 and 21 using a quantitative fluorescence-PCR (QF-PCR) approach. The abnormality rate was 5.7%. There were no misdiagnoses for nonmosaic trisomy, the amplification failure rate was 0.09% of samples, and 97% of samples received a report on the working day following sample receipt. Maternal cell contamination and mosaicism were also detected. Our data recommend a QF-PCR approach as the current method of choice for rapid aneuploidy testing.

Discordant prenatal diagnosis of trisomy 21 due to mosaic structural rearrangements of chromosome 21.

Trisomy 21 mosaicism associated with a structural rearrangement of chromosome 21 is uncommon. We report on two prenatal diagnoses in which karyotypes showed mosaicism with an aberrant cell line, including a structural rearrangement of chromosome 21. Both these cases were associated with increased nuchal translucency. Conventional and molecular cytogenetic analyses were performed on uncultured and cultured trophoblast and amniotic fluid cells. In Case 1, analysis of trophoblast cells revealed an abnormal karyotype of 47,XX,+mar.ish der(13/21)(D13Z1/D21Z1+)/46,XX. The amniocentesis showed a free non-mosaic trisomy 21. In Case 2, the trophoblast direct analysis showed a normal male karyotype whereas the long-term culture revealed a mosaicism for a dicentric long-arm isochromosome 21: 46,XY,idic(21)(p11)/45,XY,-21/46,XY. Amniocentesis showed an unbalanced non-mosaic karyotype 46,XY,idic(21)(p11) resulting therefore in trisomy for the long arm of chromosome 21. Our cases underline the importance of combining the direct analysis and long-term culture of trophoblast and emphasise the need for confirmatory studies in other tissues when mosaicism of structural rearrangement is encountered in chorionic villi. The meiotic and mitotic mechanisms of formation of these structural rearrangements of chromosome 21 are discussed.

Unexpected survival in a case of prenatally diagnosed non-mosaic trisomy 22: Clinical report and review of the natural history.

Over 30 cases of complete non-mosaic trisomy 22 have been reported in the literature in the last 20 years [Crowe et al., 1997: Am J Med Genet 71:406-413]. Twenty-two infants were liveborn with an average life expectancy of four days. Of these, nine survived beyond the first two weeks of life. The life span ranged from minutes to 3 years of age. We report a case of an infant diagnosed prenatally with complete non-mosaic trisomy 22. Options such as aggressive medical/surgical intervention or limiting interventions to symptomatic care including home hospice were discussed openly. Given this information, the family elected to provide minimal supportive measures with pediatric hospice. The infant lived for 2 months with her family before her death. Numerous medical and surgical complications are associated with this disorder. Both the family and the medical team must be prepared for in utero fetal demise, stillbirth, or for limited life expectancy. Proper management, therefore, depends upon an understanding of the diagnosis.

Prenatal diagnosis of trisomy 20 by chorionic villus sampling (CVS): a case report with long-term outcome

A case of prenatally diagnosed non-mosaic trisomy 20 in cells cultured from a chorionic villus sample (CVS)is presented. The term placental karyotype was also non-mosaic trisomy 20. The karyotype of thenewborn was 46,XY/47,XY,+20 in foreskin cultures and in a second skin culture; blood lymphocyte culture was 46,XY. Aside from diffuse, hypopigmentary swirls along the lines of Blaschko observed on hisextremities and trunk, referred to as hypomelanosis of Ito, the patient is clinically normal at 8¾ years ofage. In addition, he is one of the oldest reported cases of mosaic trisomy 20 confirmed after birth forwhich the clinical outcome has been monitored. This case demonstrates that these trisomy 20 findings are compatible with normal psychomotor development and phenotype. Copyright © 2001 John Wiley & Sons, Ltd.

Prenatal diagnosis of trisomy 20 by chorionic villus sampling (CVS): a case report with long‐term outcome

A case of prenatally diagnosed non-mosaic trisomy 20 in cells cultured from a chorionic villus sample (CVS)is presented. The term placental karyotype was also non-mosaic trisomy 20. The karyotype of the newborn was 46,XY/47,XY,+20 in foreskin cultures and in a second skin culture; blood lymphocyte culture was 46,XY. Aside from diffuse, hypopigmentary swirls along the lines of Blaschko observed on his extremities and trunk, referred to as hypomelanosis of Ito, the patient is clinically normal at 8 3/4 years of age. In addition, he is one of the oldest reported cases of mosaic trisomy 20 confirmed after birth for which the clinical outcome has been monitored. This case demonstrates that these trisomy 20 findings are compatible with normal psychomotor development and phenotype.

Relative efficiency of FISH on metaphase and interphase nuclei from non-mosaic trisomic or triploid fibroblast cultures.

Chromosome specific probes that are used in interphase fluorescence in situ hybridization (FISH) analysis are usually tested on disomic control samples. When used for preimplantation or prenatal diagnosis the aim is to detect aneuploidy, most frequently trisomy. In this study, skin fibroblast cultures from non-mosaic trisomic and triploid fetuses were analysed by FISH to assess probe efficiency regarding interphase detection of trisomy. Skin fibroblast cultures were used because they are considered to be stable in culture. FISH experiments were performed using centromeric probes for chromosomes X, Y, 18 and locus specific probes for chromosomes 13 and 21. In metaphase nuclei, the expected signals were found in 100% of at least 30 metaphases counted on each sample and this also confirmed non-mosaicism in agreement with conventional karyotyping of the fetuses. On interphase nuclei, however, only 80-89% of nuclei per population displayed the expected signals for autosomal probes and 90% for probes for the sex chromosomes. For each probe, a range of percentages was obtained that can be regarded as indicative of non-mosaic trisomy in uncultured specimens. In the case of prenatal samples, the expected presence of maternal cells may lead to a lowering of the threshold for a trisomic diagnosis. In the case of preimplantation diagnosis, the accuracy can be improved by the use of two probes per chromosome or by the analysis of two cells from each embryo.

Phenotypic recognition of maternal (mosaic) and paternal (segmental) isodisomy for chromosome 14 without a Robertsonian translocation

We report 2 cases of UPD-14 initially suspected on the basis of clinical rather than cytogenetic clues. The girl with maternal isodisomy presented prenatally with a positive triple marker screen for Down syndrome but a 46, XX karyotype on amniocentesis. Growth retardation, borderline microcephaly, hypotonia and multiple minor anomalies prompted a placental chromosome study that showed non-mosaic trisomy 14. Blood karyotype was normal and UPD-14 was confirmed at 6 weeks. She continues to have hypotonia and delayed motor but normal cognitive skills at 2-1/2 years despite the appearance of streaky hyperpigmentation on all four limbs suggesting low-grade mosaicism for a trisomic cell line.The boy with paternal isodisomy was found by prenatal ultrasound to have an omphalocele, polyhydramnios and mild skeletal disproportion but chromosomes were 46, XY in amniocytes, lymphocytes and fibroblasts. Major anomalies involving the CNS and cardiovascular system were noted postnatally. The unusual radiographic appearance of his ribs resembled that described in other reports of paternal UPD-14 (Walter, 1996; Cotter, 1997). Molecular confirmation was obtained at 7 months but a plugged tracheostomy tube caused severe anoxic brain injury and he remains hospitalized at 10 months Markers from 14pter through 14q11.2 (D14S740 and D14S1422) are biparental while those from 14q12 (D14S599 and D14S306) through 14qter are uniparental. This implies that paternally imprinted genes on chromosome 14 are located at least 20 cM from the terminal short arm

Severe intra-uterine growth retardation in a patient with maternal uniparental disomy 22 and a 22-trisomic placenta

We report on a maternal uniparental disomy of chromosome 22 in a patient with severe intra-uterine growth retardation. Karyotyping of a placental tissue revealed non-mosaic trisomy 22, whereas lymphocyte chromosomes from the newborn were normal 46,XY. Microsatellite analysis using DNA extracted from white blood cells showed maternal uniparental heterodisomy for chromosome 22. Thus, the conceptus started as maternal trisomy due to meiotic non-disjunction, and trisomy rescue occurred subsequently through loss of the paternal homologue resulting in maternal uniparental disomy. Normal phenotypes in previous reports have suggested that maternal UPD 22 has no impact on the phenotype. Thus, growth retardation in this patient was probably caused by dysfunction of the trisomic placenta.

Frequency of meiotic trisomy depends on involved chromosome and mode of ascertainment

Although maternal meiotic errors predominate in most studies of nonmosaic trisomy, studies of trisomy ascertained through confined placental mosaicism (CPM) have shown a high rate of somatic errors. However, origin of trisomy of many of the chromosomes involved in CPM has not been evaluated previously in cases ascertained through spontaneous abortions (SAs). Therefore, it was impossible to determine if the relative lack of meiotic errors in trisomy-CPM cases was a characteristic of the specific chromosome involved or due simply to ascertainment through a mosaic state. In the present study, parental and meiotic/somatic stages of origin of trisomy were determined in 89 SAs involving trisomy of chromosomes 2, 4 to 10, 12, 15, 17, and 20. Comparisons were then made to origin of trisomy in cases of confined and generalized trisomy mosaicism. Although somatic errors are generally more common in mosaic cases, this depends on the specific chromosome involved. The results suggest that there are chromosome-specific differences in the relative frequency of somatic chromosome gain or loss and/or the ability of an early somatic loss of one chromosome from a trisomic conceptus to “rescue” the pregnancy. As mean maternal age was less in the somatic than meiotic origin cases (P < 0.01), the age distribution of the study population should also influence the probability of detecting a somatic error. No phenotypic differences were apparent when cases were subdivided based on either parent or stage of origin of the trisomy. Am. J. Med. Genet. 84:34–42, 1999. © 1999 Wiley-Liss, Inc.

Frequency of meiotic trisomy depends on involved chromosome and mode of ascertainment

Although maternal meiotic errors predominate in most studies of nonmosaic trisomy, studies of trisomy ascertained through confined placental mosaicism (CPM) have shown a high rate of somatic errors. However, origin of trisomy of many of the chromosomes involved in CPM has not been evaluated previously in cases ascertained through spontaneous abortions (SAs). Therefore, it was impossible to determine if the relative lack of meiotic errors in trisomy-CPM cases was a characteristic of the specific chromosome involved or due simply to ascertainment through a mosaic state. In the present study, parental and meiotic/somatic stages of origin of trisomy were determined in 89 SAs involving trisomy of chromosomes 2, 4 to 10, 12, 15, 17, and 20. Comparisons were then made to origin of trisomy in cases of confined and generalized trisomy mosaicism. Although somatic errors are generally more common in mosaic cases, this depends on the specific chromosome involved. The results suggest that there are chromosome-specific differences in the relative frequency of somatic chromosome gain or loss and/or the ability of an early somatic loss of one chromosome from a trisomic conceptus to "rescue" the pregnancy. As mean maternal age was less in the somatic than meiotic origin cases (P < 0.01), the age distribution of the study population should also influence the probability of detecting a somatic error. No phenotypic differences were apparent when cases were subdivided based on either parent or stage of origin of the trisomy.

Trisomy 16 and trisomy 16 mosaicism: A review

A review of all prenatal and postnatal diagnoses of trisomy 16 and trisomy 16 mosaicism was carried out in the context of the current understanding of confined placental mosaicism and uniparental disomy (UPD). The prenatal detection of trisomy 16 cells is associated with a high probability of fetal death, preterm delivery, intrauterine growth retardation, and fetal anomalies. Birth defects were typical of those seen in nonmosaic partial duplications of chromosome 16. Surprisingly, anomalies were sometimes limited to a single organ and included some relatively common isolated defects such as a ventricular septal defect, hypospadias, imperforate anus, inguinal hernia, and clubfoot. The risk for abnormality appeared to be higher in those pregnancies in which trisomy 16 cells were identified in amniotic fluid compared to the detection in chorionic villi samples. Contrary to nonmosaic trisomy 16 with an excess of males, mosaic trisomy 16 shows an excess of female karyotypes. Following the prenatal detection of trisomy 16 cells, aneuploid cells are almost never found in fetal or neonatal lymphocytes. Studies on fibroblasts also often fail to confirm the presence of the abnormal cell line even in cases in which multiple anomalies are present. It is likely that trisomy 16 cells are sometimes present in the early developing embryo even though subsequent cytogenetic studies on fetal or neonatal tissues may not detect any aneuploid cells. UPD can be excluded as a mechanism for those anomalies that are common to mosaic trisomy 16 and nonmosaic partial duplications. The term "occult mosaicism" is suggested to describe the situation in which the presence of an abnormal cell line is suspected on the basis of clinical data but unproven by laboratory analysis.

Analysis of the Origin of the Extra Chromosome in Trisomy 8 in 4 Cases of Spontaneous Abortions

Objective: To determine the origin of the extra chromosome in trisomy 8 in spontaneous abortions. Methods: We analyzed 4 cases of nonmosaic trisomy 8 in 1st-trimester spontaneous abortions and their parents with DNA polymorphism analysis using microsatellite DNA markers. Results: In 3 cases the extra chromosome was maternal in origin and in 1 case paternal in origin. In 2 of the cases the nondisjunction had occurred in maternal meiosis, while the other 2 cases were consistent with a postzygotic (mitotic) origin of the additional chromosome. Conclusion: Although a small number of cases studied, these results suggest differences from the common autosomal trisomies 21, 18, 16, and 13 where the vast majority of cases are due to errors in maternal meiosis.