Trisomy Rescue Research Articles

Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue. Presentation of own results and review of the literature

Maternal uniparental disomy for the entire chromosome 7 (matUPD7) has been reported several times in Silver-Russell syndrome (SRS) and growth-restricted patients. Here we present our results from the analysis of an abortion with confined placental mosaicism (CPM) for trisomy 7 which showed a maternal meiotic origin of the trisomy in the placenta and rescue to maternal UPD7 in foetal membrane. Furthermore, two newly detected SRS cases with maternal UPD7 revealed isodisomy and partial heterodisomy, respectively. Summarising these results with those published previously on the origin of UPD7, similar numbers of isodisomy ( n=11) and cases with complete or partial heterodisomy ( n=12) have been reported. In respect to the different formation mechanisms of UPD, complete isodisomy should be the result of a post-zygotic mitotic segregation error, whereas heterodisomic UPDs should be caused by trisomic rescue after meiotic non-disjunction events. In maternal UPD7, 50 % of cases seem to be caused by post-zygotic mitotic segregation errors, which is similar to the situation in trisomy 7. This result corresponds to the situation in trisomy 8 but is in contrast to observations in the frequent aneuploidies. Thus, the different findings in these aberrations reflect the presence of multiple factors that act to ensure normal segregation, varying in importance for each chromosome.

A third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report a boy with hypotonia, a Prader-Willi syndrome (PWS) facial phenotype, a large muscular VSD and a PDA due to maternal isodisomy for chromosome 15 with mosaic trisomy 15. At 18 months of age, his height, weight and head circumference are below the 5th %tile and his development is in the moderate mental retardation range. While our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we believe, based on a review of other cases of trisomy 15 mosiacism, that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with the PWS can have one of three similar but distinctive phenotypes depending on the etiology of their condition. Patients with paternal deletions have the typical PWS phenotype with mild to moderate mental retardation and significant behavioral problems; patients with maternal UPD have a milder physical phenotype, better cognitive function and fewer behavioral abnormalities; and patients with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease, severe growth and development delays. We propose that incomplete “trisomic rescue” with residual mosaic trisomy 15 leads to this third and most “severe” Prader-Willi phenotype. Thus the phenotypic spectrum of the Prader-Willi syndrome is at least in part explainable by the varying molecular etiologies. These phenotype/genotype differences are useful both to guide the evaluation of patients with suspected PWS and to provide prognostic counseling for families.

Severe growth retardation and limb anomalies in a boy with 47,XY,+r(7) and maternal uniparental disomy for chromosome 7

Russell-Silver syndrome (RSS) is genetically heterogeneous with maternal uniparental disomy (mat UPD) reported in approximately 10% of cases. We report a young boy with severe growth retardation and asymmetric limb anomalies found to have maternal UPD for chromosome 7 and a small ring 7 [47, XY,upd(7)mat,+r(7)]. G.D. was the 1.85 kg SGA product of a 38 week gestation to a 17 year old P0 mother. At 31 months of age, his height was 46.7 cm (5th% for birth), weight 4.29 kg (50th % for 1 month), and head circumference 47 cm (50 % for 1 year). G.D. has asymmetrically shortened femurs and absence of the left fibula. His thumbs appear digitalized and he has decreased range of motion in his elbows. He is normocephalic with a small jaw and is moderately developmentally delayed. G-banded chromosome study showed a tiny marker (ring) containing a centromere and very little euchromatin, by spectral karyotyping the marker was identified as derived from chromosome 7. Parental karyotypes are normal. Because of his severe growth retardation and low birth weight, molecular analysis for UPD(7) was performed, revealing maternal isodisomy for most of chromosome 7 due to a maternal meiotic II error. There was a non-terminal region of heterodisomy in the q arm due to a double crossover at meiosis I. The most likely explanation of the r(7) is unsuccessful trisomy rescue in which the paternal homologue was not completely lost, but rather was retained vestigially in the form of a tiny ring chromosome. A similar mechanism has been hypothesized to explain the occurrence of cases of UPD(15) + mar(15) reported in the literature. To our knowledge, this is only the second report of mat UPD(7)+r(7) in a child. The other patient was mosaic for the ring with a less severe phenotype than our case. Studies on cases of UPD(15)+mar(15) indicate that the size of the marker directly correlates with the severity of the physical and developmental phenotype. This does not hold true for our patient as he has a severe RSS phenotype and a very small marker, leading to speculation on other possible causes including homozygosity for a deleterious gene on 7.

Isochromosome 1q as the Sole Chromosomal Abnormality in Two Fetal Teratomas: Possible Trisomic or Tetrasomic Zygote Rescue in Fetal Teratoma with an Additional Isochromosome 1q

An isochromosome of the long arm of chromosome 1 leading to tetrasomy 1q was detected as the sole chromosomal aberration in two cases of fetal teratoma arising from the oral cavity. This type of teratoma is extremely rare and has seldom been investigated cytogenetically. Studies of DNA markers in the tumor, normal fetal skin, and parental cells demonstrated that in both cases the additional 1q material was of maternal origin. In one of the patients, the teratoma had maternal 1q marker alleles that were not found in the fetal body cells. This implies that the tumor was not derived in a direct way from the fetal body tissue; instead, the chromosomally-normal fetus might be the result of some trisomic or tetrasomic zygote rescue mechanism.

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.

Abnormal phenotypes in uniparental disomy (UPD): Fundamental aspects and a critical review with bibliography of UPD other than 15

Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from only one parent. The bases are always two events, either two meiotic, or one meiotic and one mitotic, or two mitotic. An aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal disorders in females, and father-to-son transmission of X-linked traits are the possible and yet repeatedly documented consequences sometimes associated with unfavorable handicaps. Fertilization of a disomic (=hyperhaploid) gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue) is the most frequently supposed mechanism of formation and might result in mosaicism in the placenta or even in a subset of fetal tissues. This low-level mosaicism can remain undetected and renders the delineation of a phenotype more difficult. Therefore, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, the nonmendelian inheritance of monogenic disorders, or by a combination of all these factors. A survey of all reported cases demonstrates a preponderance of maternal versus paternal UPD (approximately 3:1) and an unequal chromosomal distribution. Most likely, deleterious trisomy mosaicism, imprinted genes, the nature of the chromosome itself, the clinical interest in a single chromosome, and, last but not least, an ascertainment bias are therefore responsible.

Uniparental disomy with and without confined placental mosaicism: a model for trisomic zygote rescue

In the population of children born after prenatal cytogenetic investigation in chorionic villi at our department from 1992 to 1995 (N = 3940), three are known to us with uniparental disomy. One case of maternal heterodisomy 16 was prenatally discovered because of trisomy 16 in direct chorionic villi with subsequently normal amniotic fluid cells. The other two had normal karyotypes in chorionic villi. Maternal heterodisomy 15 was postnatally detected in one of them because of Prader-Willi syndrome. Maternal hetero/isodisomy 16 was accidentally encountered in the other case in the course of prenatal DNA analysis of the tuberous sclerosis complex 2 region at 16p13.3. A model is presented for the understanding of the various combinations of karyotypes in direct chorionic villi, cultured chorionic villi and the fetus in the case of successful and unsuccessful trisomic zygote rescue.

Uniparental disomy with and without confined placental mosaicism: a model for trisomic zygote rescue

Uniparental disomy with and without confined placental mosaicism: a model for trisomic zygote rescue

Prospective Prenatal Diagnosis of Prader–Willi Syndrome due to Maternal Disomy for Chromosome 15 following Trisomic Zygote Rescue

We present a prenatal predictive diagnosis of Prader-Willi syndrome arising as a result of maternal heterodisomy for chromosome 15. The diagnosis arose following chorionic villus sampling which showed a mosaic trisomy 15 karyotype with a chromosomally normal follow-up amninocentesis. Molecular studies on DNA extracted from cultured amniocytes showed no evidence of a paternal allele at two widely separated loci and this was taken as evidence of maternal disomy predictive of Prader-Willi syndrome in the fetus.

European collaborative research on mosaicism in CVS (EUCROMIC)--fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy.

Cytogenetic information on cells from cytotrophoblast, villus mesenchyme, and one or more fetal tissues was available for 192 gestations with mosaicism or non-mosaic fetoplacental discrepancy involving a single autosomal trisomy in the chorionic villus sample (CVS), registered in a collaborative study (EUCROMIC) during the period 1986-1994. In order to identify predictors of confined placental mosaicism (CPM), generalized mosaicism and/or uniparental disomy (UPD), distribution of the mosaic and nonmosaic aneuploid cell lines in the different fetal and extrafetal cell lineages were analyzed. Data were related to existing hypotheses on mechanisms leading to fetoplacental discrepancies and early extraembryonic cell differentiation. Trisomy 21 mosaicism was the one most frequently confirmed in the fetus. Non-mosaic trisomy 13, 18, and 21 in the villus mesenchyme indicated the presence of a trisomic cell line in the fetus proper. Non-mosaic trisomy 2, 7, and 16 in villus mesenchyme was always found with concomitant mosaic or non-mosaic trisomy in the cytotrophoblast, but was never recovered in the fetus. Mosaic trisomy 3, 7, and 20 was predominantly restricted to the cytotrophoblast, mosaic trisomy 2 to the villus mesenchyme. Trisomies 15 and 16 were most often found in both cytotrophoblast and villus mesenchyme and not in fetal cells. This supports the hypothesis that mosaicism/discrepancy for trisomies 15 and 16 results more often than for the other trisomies from trisomic zygote rescue, enhancing their risk for UPD. We recommend, due to the risk of fetal trisomy, amniocentesis in all gestations involving mosaic autosomal trisomy in villus mesenchyme. In gestations with mosaic or non-mosaic autosomal trisomy in both cytotrophoblast and villus mesenchyme we recommend, in order to exclude fetal trisomy and/or UPD, depending on the chromosome involved, further examination by amniocentesis, ultrasound and/or test for UPD. We also recommend, due to a small but not negligible risk of false negative and false positive diagnoses, not to solely use direct preparation.

Trisomy 15 rescue with jumping translocation of distal 15q in Prader-Willi syndrome.

We report a patient with Prader-Willi syndrome (PWS) and mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter. A maternal uniparental heterodisomy...

Prader-Willi syndrome in a child with mosaic trisomy 15 and mosaic triplo-X: a molecular analysis.

A 3.3 year old girl with Prader-Willi syndrome (PWS) and mosaicism for two aneuploidies, 47,XXX and 47,XX,+15, is presented. The triplo-X cell line was found in white blood cells and...

Trisomy 7 CVS mosaicism: pregnancy outcome, placental and DNA analysis in 14 cases.

Prenatal diagnosis by chorionic villus sampling (CVS) documents placental chromosomal mosaicism in approximately 2% of viable pregnancies at 9-12 weeks of gestation and can involve various chromosomes and placental cell lineages. Confined placental mosaicism (CPM) is the result of postzygotic mitotic errors occurring in either diploid or trisomic zygotes. With trisomic zygote rescue, depending on the parental origin of the chromosome which is lost, uniparental disomy (UPD) or biparental disomy (BPD) may arise [Kalousek et al., Am J Hum Genet 52: 8-16, 1993]. In this paper, we present 14 pregnancies which were diagnosed by CVS as mosaic trisomy 7. All follow-up amniocenteses showed a normal diploid karyotype. Using both classical cytogenetics and interphase analysis, studies of term placentae showed variable levels of trisomy 7. DNA analysis was performed in nine cases to determine whether the diploid fetus had BPD 7 or UPD 7. Fetal UPD 7 was present only in one case; in eight other cases biparental inheritance was demonstrated. DNA analysis to establish the origin of trisomy 7 in the placenta was fully informative in six cases. One trisomy resulted from a meiotic error and was associated with fetal UPD 7, while the rest were somatic in origin. It is difficult to compare the effect of CPM for trisomy 7 to other trisomies confined to the placenta, as for most chromosomes there are few available cases. It appears that intrauterine fetal growth is not greatly affected by the presence of a trisomy 7 cell line in the placenta. This finding is in contrast to the serious effect of high levels of trisomy 16 within the placenta on fetal intrauterine growth in a series of well-documented cases of CPM 16 [Kalousek et al. 1993].

An audit of trisomy 16 in man.

Sufficient information is now available from the literature to produce an audit of trisomy 16, in a theoretical cohort of 100,000 recognized pregnancies, from gametogenesis to term and onwards. Recent reports of premature separation of chromosome 16 bivalents during maternal meiosis I provide a novel mechanism for generation of this aneuploidy. Most, if not all, errors resulting in recognized mosaic and non-mosaic trisomy 16 pregnancies investigated using polymorphic DNA markers appear to originate at that stage. The incidence of this maternally derived trisomy 16 in the late first trimester is equivalent to 1500 cases in 100,000 recognized pregnancies, a figure which now corresponds very closely to the reinterpreted oogenesis data. Most trisomy 16 pregnancies are lost around 12 weeks' gestation, but of the order of 10 per cent (120-150 in this audit) undergo reduction to disomy, with 30 of these excluding aneuploidy from the fetal cell lineage (trisomic zygote rescue) and continuing into the second trimester. Maternal uniparental disomy (UPD) in one-third of this latter group is associated with loss later in pregnancy or severe intrauterine growth retardation, but can be compatible with a viable pregnancy. Adverse pregnancy outcomes are not restricted to those with UPD. Analysis of reports of confined placental mosaicism for chromosome 16 without associated UPD indicates that the presence of high levels of trisomic cells in the placenta alone consistently produces a more variable inhibition of fetal growth, which may also, in cases, be associated with late pregnancy loss.

Confined placental mosaicism and intrauterine fetal development

Chromosomal mosaicism is the presence of two or more cell lines with different chromosomal complements in an individual derived from a single zygote (which is distinguishable from chimaerism in which an individual is derived from more than one zygote). Mosaicism may involve a number of different karyotypic abnormalities including those for whole sets of chromosomes (polyploidy, including triploidy and tetraploidy), trisomies, sex chromosomal anomalies and chromosomal rearrangements. Mosaicism itself may be present in all the tissues of the body and placenta, or it may only be seen in certain tissues or may be restricted to only the placenta and extraembryonic membranes. The type of mosaicism seen depends upon the stage of development at which it originated, the tissue types to which the abnormal cell lines were distributed and the cell cycle times of both the normal and abnormal cells. The phenotypic effects or consequences of chromosomal mosaicism may be dramatic. During the pregnancy, high levels of mosaicism are seen in early abnormal preimplantation embryos, spontaneous abortions, intrauterine growth restriction and intrauterine fetal death. However, not all cases of mosaicism are serious and the presence of a normal cell line may dilute the effects of an abnormal cell line to such an extent that in many cases mosaicism will remain undetected because the consequences are not severe. Investigations of chromosomal mosaicism were, until recently, restricted to those cells which could be induced to divide and be karyotyped from metaphase analysis. Advances in molecular genetics and cytogenetics have made possible the identification of chromosomal abnormalities, specifically mosaicism in interphase cells. The identification of abnormalities such as confined placental mosaicism and its association with uniparental disomy has led to the recognition that chromosomal mosaicism plays a major role in abnormal human development and dysmorphology (Hall, 1990). An understanding of mosaicism and the role of the placenta during development, including the phenomenon of trisomic zygote rescue, is helping to cast light on problems in prenatal diagnosis, many of which involve confined placental mosaicism.