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.     

Supernumerary small marker chromosome (SMC) and uniparental disomy 22 in a child with confined placental mosaicism of trisomy 22: trisomy rescue due to marker chromosome formation

Trisomy rescue is one of various proposed mechanisms in formation of supernumerary small marker chromosomes (SMC) and uniparental disomy (UPD). In the present report a small de novo marker chromosome derived from chromosome 14 or 22 was diagnosed at prenatal diagnosis due to maternal age. Follow up investigations at birth revealed mosaicism 47,XX,+mar/46,XX. Using FISH, the marker was positive for the probe D14/22Z1, but negative for the probes midi 54 and D22Z4. Using three informative markers both chromosomes 22 were shown to be inherited from the mother (UPDmat). The results are consistent with nondisjunction at maternal meiosis I. The girl is 18 months old now and phenotypically normal. Cardiac and abdominal malformations were excluded by sonographic examinations. Motor and mental development is according to or ahead of developmental milestones (free walking with 10 months, first words at 12 months). The case confirms that maternal UPD 22 most likely is not associated with clinical abnormalities. According to FISH results, UPD 22, and 47,XX,+22 in the placenta, we conclude that the SMC was derived from alpha satellite sequences of chromosome 22. This case for the first time gives evidence that early postzygotic reduction of a chromosome to a small marker chromosome is a real existing mechanism to rescue a conceptus with trisomy.     

A rare case: mosaic trisomy 22.

A 9-year-old female child of healthy parents (mother: 43 years, father: 44 years) was referred to our center because of severe mental retardation. While pedigree analysis was not contributory, two older sibs were normal and healthy. Physical examination revealed facial dysmorphism, microcephaly and hyperflexibility of all joints. Her chromosome constitution showed a mosaic pattern; mos 46,XX[98]/47,XX,+22[2]. So skin biopsy was performed and mosaic trisomy 22 was confirmed with FISH analysis (46,XX[73]/47,XX,+22[27]). Physical features of this case seemed consistent with her mosaic constitution. This report would be a demonstrative example to show the significant contribution of FISH in states of mosaicism.     

Chromosome 14 maternal uniparental disomy in the euploid cell line of a fetus with mosaic 46,XX/47,XX,+14 karyotype

We investigated the parental origin of the extra chromosome 14 and of the two chromosomes 14 of the euploid cell line, in a case of fetal mosaicism 46,XX/47,XX+14 diagnosed at amniocentesis. Molecular analysis of five polymorphic loci of the short tandem repeat type was performed. Markers D14S43 and D14S49 showed the presence of maternal uniparental disomy of chromosome 14 in the apparently normal cell line. The distribution of the markers analysed along the chromosome suggests maternal heterodisomy with a large isodisomic segment in the telomeric region, possibly caused by meiotic crossing-over.     

Supernumerary marker chromosome 5 diagnosed by M-FISH in a child with congenital heart defect and unusual face

We describe a female patient with a small supernumerary marker chromosome (sSMC) present in mosaic and characterized in detail by fluorescence in situ hybridization (FISH) using all 24 human whole chromosome painting probes, multicolor banding (MCB) and subcentromere specific multicolor FISH (subcenM-FISH). The sSMC was demonstrated to be derived from chromosome 5 and the karyotype of our patient was as follows: 47,XX,+mar.ish r(5)(::p13.2 approximately p13.3-->q11.2::) [60%]/46,XX [40%]. Partial trisomy for the proximal 5p and q chromosomal regions is a rare event. A critical region exists at 5p13 for the phenotype associated with duplication 5p. As far as we know, eight similar cases have been published up to now. We describe a new case which, to our knowledge, is the first characterized in such detail. The role of uniparental disomy (UPD) in cases of SMC is also discussed.     

Recurrent proximal 18p monosomy and 18q trisomy in a family with a maternal pericentric inversion of chromosome 18

We report a recurrent partial monosomy of 18p10-->11.2 and proximal partial trisomy of 18q10-->21.3 caused by a maternal pericentric inversion of chromosome 18, involving breakpoints p11.2 and q21q21.3 Based on cytogenetics and FISH analysis, we speculate that the recurrent chromosome abnormality in the proband and in the fetus was the result of a translocation, possibly in a germ cell or germ cell precursor, between the maternal normal 18 and her inverted 18, resulting in maternal germinal mosaicism, i.e. 46,XX,inv(18)/46,XX,t[18;inv(18)][q10;q10]. The unbalanced karyotype of the proband and the fetus is 46,XY,+18,der[18;inv(18)][q10;q10]. To the best of our knowledge, there are no reports of this combination of proximal 18p monosomy and proximal 18q trisomy. The other interesting observation was association of Hirschsprung's disease in the proband.     

Uniparentale Disomien und Mosaike

Of the various mechanisms of formation of uniparental disomy (UPD) discussed in the literature, the mechanism of trisomy rescue is mostly prone to mosaicism from a trisomy cell line and from a disomy 46, XN uniparental cell line. Therefore, low level or undetected mosaicism has been assumed for a significant number of UPD cases. The clinical consequences of trisomy/UPD mosaicism probably depend on the chromosome involved and the proportional content in individual tissues. As the trisomy cell line of some mosaics might have a disadvantage in biological selection it might not be detected in routine lymphocyte investigations. For evaluation of the clinical relevance in the case of an imprinted chromosome the associated imprinting disorder must also be considered. In a postnatal setting analysis of UPD is indicated in the case of clinical, cytogenetic and molecular data. In the prenatal setting genetic counseling of the parents should be offered prior to any laboratory testing. In total, the impact of mosaicism associated with UPD has to consider the affected chromosome, the associated phenotype, the mechanism of formation and the laboratory method used.     

Complex rearrangements of chromosome 15 in two patients with mild/atypical Prader Willi syndrome

Multiple mechanisms are responsible for the development of Prader Willi syndrome (PWS), the most common genetic cause of obesity in childhood. Molecular findings are usually deletions and uniparental disomy (UPD) of the 15q11-13 region. Rarely, structural rearrangements of the pericentromeric region of chromosome 15 are also detected. Two cases with mild PWS phenotype and complex maternal UPD identified by microsatellite analysis are described: the first patient had uniparental iso and heterodisomy and the second displayed biallelic inheritance and uniparental isodisomy.     

Rare case of XX/XY mosaicism and trisomy 13 in early prenatal diagnosis

Coexistence of XX/XY sex mosaicism and autosomal trisomy in prenatal diagnosis is particularly rare. Herein, we report the first, to our knowledge, case of a fetus with cyclopia, ambiguous genitalia and a 47,XX,+13,inv9[47]/47,XY,+13[13] karyotype detected at 13 weeks of gestation after chorionic villus sampling. Molecular analysis after prenatal diagnosis suggests that this is a case of sex mosaicism coexisting with trisomy 13, rather than chimera.     

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.     

Familial partial trisomy 15.

A family, including two sibs with partial trisomy 15 is described. Maternal chromosome analysis revealed 46,XX/47,XX,+15q-, mosaicism. These findings are discussed in relation to seventeen previously published cases, some of which were sporadic and others due to maternal balanced translocation.     

An infant with Turner-Down aneuploidy and massive capillary hemangioma of the orbit: a case report with review

We report on a case of double aneuploidy involving Down and Turner cell lines in a female child with a massive capillary hemangioma of the left orbit and mild clinical features of Down syndrome. Cytogenetic findings with G-banding revealed mosaicism in her peripheral blood, i.e. mos45,X[48]/47,XX,+21[28]/46,XX[12/47,XXX[12]. Mosaicism of such nature is rare and to our knowledge the present case is the first reported of Turner-Down double aneuploidy mosaicism associated with an orbital capillary hemangioma. An annotated bibliography of earlier reported cases with documented karyotyping is also included.     

Uniparental disomy and the phenotype of mosaic trisomy 20: a new case and review of the literature

Mosaic trisomy 20 is one of the most commonly reported chromosome abnormalities detected prenatally, but is rare postnatally. Many studies have hypothesized that uniparental disomy (UPD) may play a role in phenotype variability, but this has not been widely studied. Here we report an additional case of mosaic trisomy 20 with altered pigmentation, in which UPD was not found, and we review the literature.     

Uniparental disomy for chromosome 16 in humans.

The association between chromosomal mosaicism observed on chorionic villus sampling (CVS) and poor pregnancy outcome has been well documented. CVS mosaicism usually represents abnormal cell lines confined to the placenta and often involves chromosomal trisomy. Such confined placental mosaicism (CPM) may occur when there is complete dichotomy between a trisomic karyotype in the placenta and a normal diploid fetus or when both diploid and trisomic components are present within the placenta. Gestations involving pure or significant trisomy in placental lineages associated with a diploid fetal karyotype probably result from a trisomic zygote which has lost one copy of the trisomic chromosome in the embryonic progenitor cells during cleavage. Uniparental disomy would be expected to occur in one-third of such cases. Trisomy of chromosome 7, 9, 15, or 16 is most common among the gestations with these dichotomic CPMs. Nine pregnancies with trisomy 16 confined to the placenta were prenatally diagnosed. Pregnancy outcome, levels of trisomic cells in term placentas, and fetal uniparental disomy were studied. Intrauterine growth retardation (IUGR), low birthweight, or fetal death was observed in six of these pregnancies and correlated with high levels of trisomic cells in the term placentas. Four of the five cases of IUGR or fetal death showed fetal uniparental disomy for chromosome 16. One of the infants with maternal uniparental disomy 16 had a significant malformation (imperforate anus). All infants with normal intrauterine growth showed term placentas with low levels of trisomic cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prenatally identified case of mosaicism of chromosome 16 trisomy

We present the prenatally identified case of mosaicism of chromosome 16 trisomy. A patient with the pregnancy complicated in the first trimester by the threat of breaking was refered to the high risk group according to the results of the screening program. The ultrasonic research revealed a number of phenotypical pathologies in 19-weeks-old fetus such as congenital heart disease (ventricular septal defect), hyperechoic bowel, single umbilical artery and some other ones. Cytogenetical and FISH analyses of the placental villi revealed karyotype with chromosome 16 trisomy. The further research of amniotic fluid cells revealed the karyotype of fetus as mos47,XX,+16 / 46,XX. The pathologoanatomic research of the abortus has verified the multiple congenital malformations.     

The impact of imprinting: Prader-Willi syndrome resulting from chromosome translocation, recombination, and nondisjunction.

Prader-Willi syndrome (PWS) is most often the result of a deletion of bands q11.2-q13 of the paternally derived chromosome 15, but it also occurs either because of maternal uniparental disomy (UPD) of this region or, rarely, from a methylation imprinting defect. A significant number of cases are due to structural rearrangements of the pericentromeric region of chromosome 15. We report two cases of PWS with UPD in which there was a meiosis I nondisjunction error involving an altered chromosome 15 produced by both a translocation event between the heteromorphic satellite regions of chromosomes 14 and 15 and recombination. In both cases, high-resolution banding of the long arm was normal, and FISH of probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of this material. Chromosome heteromorphism analysis showed that each patient had maternal heterodisomy of the chromosome 15 short arm, whereas PCR of microsatellites demonstrated allele-specific maternal isodisomy and heterodisomy of the long arm. SNRPN gene methylation analysis revealed only a maternal imprint in both patients. We suggest that the chromosome structural rearrangements, combined with recombination in these patients, disrupted normal segregation of an imprinted region, resulting in uniparental disomy and PWS.     

Structural chromosome abnormalities in Down syndrome: a study of two families.

Two families were ascertained through a proband with Down syndrome and a structural rearrangement involving two chromosomes 21. It is suggested that in one patient the chromosome is an isochromosome formed by misdivision of the centromere of a maternal telocentric chromosome 21 and that in the other a Robertsonian translocation involving chromosome 21 was inherited from the mother, who is a 46,XX/46,XX, -21,+t(21q21q) mosaic. The origin of the mosaicism is discussed and considered to be likely to be the result of breakage and reunion at the chromatid, rather than the chromosome, level.     

Origin of acrocentric trisomies in spontaneous abortuses

Summary A total of 33 spontaneous abortuses with various acrocentric trisomies were studied for the origin of the extra chromosomes using Q- and R-band polymorphisms as markers. Eleven trisomic abortuses were informative: nine trisomic abortuses (one with trisomy 13, three with trisomy 21, and five with trisomy 22 including one with a 46,XX/47,XX,+22 mosaicism) originated at maternal first meiosis; a 21-trisomic abortus resulted from an error at maternal second meiosis (or first mitosis); and a 13-trisomic abortus was of maternal first or second meiotic origin. The abortus with mosaic trisomy 22 started as a 22-trisomic zygote resulting from an error at maternal first meiosis, followed by a mitotic (in vivo or in vitro) loss of the paternally derived chromosome 22.     

Maternal uniparental disomy 16 and genetic counseling: new case and survey of published cases

Uniparental disomy (UPD) is the occurrence of both homologous chromosomes from one parent. Maternal UPD(16) is the most often reported UPD other than UPD(15); almost all cases are associated with confined placental mosaicism (CPM). Most of maternal UPD(16) cases are characterised by intrauterine growth retardation (IUGR) and different congenital malformations. Maternal UPD(16) has therefore been suspected to have clinical effects: however, the lack of uniqueness and specificity of the birth defects observed suggests that the phenotype may be related in parts to placental insufficiency. We report on a new case of maternal UPD(16) associated with low level trisomy 16 mosaicism in placenta and fetus. IUGR was noticed at 19 gestational weeks and the fetus died intrauterine. Apart from different craniofacial dysmorphisms she showed anal atresia. While IUGR is probably associated with trisomy 16 mosaicism, anal atresia is more characteristic for maternal UPD( 16). Considering the features in our patient as well as those in maternal UPD (16) cases from the literature, indications for UPD (16) testing can be defined: They include trisomy 16 mosaicism, IUGR and congenital anomalies (anal atresia, congenital heart defects). However, there is an overlap of clinical signs in mosaic trisomy 16 cases mosaic for maternal UPD(16) as opposed to those mosaic for biparental disomy 16. The management of trisomy 16 pregnancies should not differ from those in which maternal UPD(16) is confirmed. Therefore, a prenatal testing for UPD(16) is not useful, but it should be offered postnatally. The molecular genetic proof of maternal UPD(16) excludes an increased recurrence risk for the family for further pregnancies.