Experiences with unexpected structural chromosome aberrations in prenatal diagnosis in a danish series

The investigation of 5547 prenatal diagnoses showed 31 unexpected structural chromosome rearrangements. These included 3 Robertsonian translocations, 14 reciprocal translocations and 14 inversions. A11 were balanced, including 5 de novo rearrangements. In 3 of these cases an induced abortion was performed and in 2 cases children without detectable malformations were delivered.     

Incidence of fetal chromosome abnormalities in 2264 low-risk women

Among a population of 6305 pregnant women, aged 25 to 34 years and estimated to be at no increased risk of genetic disease in the fetus, 4606 women participated in a randomized controlled trial of genetic amniocentesis between 1980 and 1984. In the study group having amniocentesis (2264 women), 23 fetal chromosome abnormalities (1.0 per cent) were found: eight autosomal aneuploidies, seven sex chromosome aneuploidies, seven balanced structural rearrangements and one case of a marker some. The structural rearrangements and the marker chromosome were all shown to be inherited. The study group seemed representative for the whole population of younger women at low genetic risk. Therefore, a 1.0 per cent total rate of fetal chromosome abnormalities, consisting of one-third autosomal aneuploidies, one-third sex chromosome aneuploidies and one-third structural rearrangements, may be expected in the second trimester in younger low-risk women. In the same period of time, 562 women in the same age group were offered amniocentesis because of an estimated increased risk of fetal genetic disease. The total rate of fetal chromosome abnormality in this ‘high-risk’ group was 0.9 per cent and thus no different from the rate in the low-risk group.     

Characterization of marker chromosomes by microdissection and fluorescence in situ hybridization

We characterized by microdissection and fluorescence in situ hybridization (FISH) two marker chromosomes: (1) a de novo, acrocentric marker chromosome detected in 88 per cent of the amniotic fluid cells of one of two physically and developmentally normal twins; and (2) a metacentric marker chromosome present in a phenotypically normal female. Analysis of FISH probes developed from the marker chromosomes indicated that the marker chromosomes in cases 1 and 2 were del(14)(q11) and a derivative chromosome from a Robertsonian translocation, respectively. Microdissection in combination with FISH may prove to be a valuable technique in determining the chromosomal origin of de novo marker chromosomes and unbalanced structural rearrangements detected during prenatal diagnosis.     

Outcome of cases of de novo structural rearrangements diagnosed at amniocentesis

The frequency of de novo rearrangements at amniocentesis was determined in 76952 prenatal diagnoses from centres in the United States. Rates for balanced rearrangements are slightly greater than rates previously reported in the newborn, possibly because banding studies were not used in the latter. Rates for unbalanced rearrangements are considerably higher in the amniocentesis data not only because banding was used but also because a substantial loss of abnormal conceptions is to be expected between amniocentesis and birth. The higher frequency of cases with supernumerary markers at amniocentesis is unexplained. A review of 66 apparently balanced de novo rearrangements found at amniocentesis revealed evidence of abnormality in five; in four of these the abnormality was noted in the abortus. The number of cases observed is still too small to rule out a risk of abnormality no greater than the usual rate of abnormalities at birth. Abnormalities were detected in 6 of 10 cases with unbalanced de novo rearrangements. In 33 cases of non-familial supernumerary chromosomes 6 (18.2 per cent) showed abnormality. Non-satellited markers appeared to have a higher rate of abnormality than satellited markers but the difference is not statistically significant. Further studies and improved follow-up of de NOVO cases diagnosed at amniocentesis are required.     

Prenatal diagnosis and postnatal follow-up of a child with two de novo unrelated balanced reciprocal translocations

Two unrelated, apparently balanced, reciprocal translocations involving chromosomes 3 and 17, and 10 and 15 were found in cultured amniotic fluid cells from a 41-year-old 10-gravida. Chromosome analysis of peripheral blood lymphocytes of both parents revealed normal katryotypes. Post-partum examination of lymphocyte cultures from the proband confirmed the chromosome rearrangements. The child showed normal development during follow-up examinations up to the age of 4 years.     

A fetus with a chromosome 13 ring and placenta with chromosome 13 rod/ring mosaicism

A fetus was identified by prenatal cytogenetic diagnosis as having a karyotype 46,XY,r(13) (p11q13). Termination of the pregnancy yielded a severely malformed fetus. Fetal abnormalities included anencephaly, imperforate anus and urethral meatus, severe talipes, syndactyly, cardiac defects and other anomalies. Confirmatory studies on cultured placental villi cells indicated a second cell line, 46,XY, −13,+ 13qter→cen::13ql3→qter. This cell line was not detectable in cells derived from the fetus despite extensive studies. It seems likely that the two cell lines arose simultaneously with selection favouring the 46,XY,r(13) line. How the chromosome rearrangements may have arisen is discussed. We are unaware of other cases where a cell line identifiable by a chromosome abnormality appeared to be confined to placental tissue. However, studies on placental tissue may be helpful in understanding the origin of other unbalanced de novo rearrangements.     

A collaborative study of the segregation of inherited chromosome structural rearrangements in 1356 prenatal diagnoses

A collaborative study involving 71 European prenatal diagnosis centres has collected 1356 observations on the karyotype of fetal cells in diagnoses performed in couples in which a parent had a balanced structural rearrangement. The segregations of the inherited chromosome structural rearrangement were analysed in relation to the types of rearrangement, to the sex of the carrier parent, the methods of ascertainment of the anomaly in the family, the chromosomes involved and the potential imbalance of the anomaly. Wide differences in the incidence of unbalanced fetuses were observed in relation to these criteria, and these results can be used in counselling parents with balanced rearrange- ments. Distortions in segregation of normal versus balanced karyotypes were observed in some types of anomalies.     

Nuchal translucency thickness and outcome in chromosome translocation diagnosed in the first trimester

In order to determine the significance of nuchal translucency thickness on the subsequent natural history of first-trimester fetuses with a chromosome translocation, seven consecutive cases diagnosed between 11 and 13 weeks of gestation were reviewed. Nuchal translucency measurements were successfully obtained before chorionic villus sampling (CVS) in all cases. Three fetuses had an unbalanced translocation and all were associated with increased nuchal translucency and multiple anomalies at the detailed second-trimester scan. There were no survivors in this group. The remaining four fetuses had a balanced translocation; all had normal nuchal translucency thickness and no structural anomalies were detected in the second trimester. Three of these fetuses were born at ≥35 weeks of gestation and were phenotypically normal. However, an unexpected single fetal demise occurred in a dichorionic twin pregnancy at 28 weeks of gestation. It is concluded that nuchal translucency measurements provide important prognostic information on pregnancy outcome in first-trimester fetuses with a chromosome translocation. In parents with a known balanced translocation, the detection of increased nuchal translucency at 11–14 weeks of gestation is associated with unbalanced translocations, structural anomalies and poor pregnancy outcome. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a de novo complex chromosomal rearrangement involving four chromosomes

A complex chromosome rearrangement, apparently a balanced translocation involving chromosomes 4,6, 15 and 16, was found in cultured cells of amniotic fluid from a 32–year-old primigravida who requested amniocentesis for prenatal diagnosis because of a family history of mental retardation. Chromosome analysis of peripheral blood from both parents were normal. The couple was counselled for the prenatal diagnosis of this de novo complex translocation and, subsequently, elected to terminate the pregnancy. Post-mortem examination revealed a 23–week fetus with intrauterine growth retardation. The identical chromosome rearrangement was subsequently confirmed in cultured fibroblasts from skin and cord obtained from the abortus. To our knowledge, this is the first report where routine prenatal diagnosis revealed a fetus with a balanced complex chromosomal rearrangement involving four chromosomes of de novo origin.     

Rapid interphase analysis for prenatal diagnosis of translocation carriers using subtelomeric probes

Interphase fluorescence in situ hybridization (FISH) has become an accepted laboratory technique for the rapid and preliminary prenatal assessment of chromosome aneuploidy. The introduction of subtelomeric FISH probes now allows for the molecular–cytogenetic analysis of terminal chromosome rearrangements. In a prospective study, we examined the prenatal use of subtelomeric probes on interphase cells to rapidly detect the carrier status of a fetus when a parent carried a known reciprocal or Robertsonian chromosome translocation. Three of the cases were identified as being abnormal. All cases were confirmed by routine cytogenetic analysis. These findings clearly demonstrated the utility of this technique and these probes to rapidly and correctly identify balanced and unbalanced chromosome anomalies of a fetus that could result from parental translocations. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal investigation of a 45,X/46,X,r(?) karyotype in amniocytes using fluorescence in situ hybridization with an X-centromeric probe

The karyotype of cultured amniotic fluid cells obtained on the indication of advanced maternal age was shown to be a mosaic 45,X/46,X,r(?). The small size and banding pattern made it difficult to determine whether the ring was derived from and X or a Y chromosome, or even from an autosome. By using an X-centromeric probe and fluorescence in situ hybridization (FISH), we demonstrated the ring to have an X centromere. Thus, a more complete genetic counselling was possible. This confirms the usefulness of FISH in identifying and characterizing this and other chromosome rearrangements in prenatal diagnosis.     

The importance of investigating for uniparental disomy in prenatally identified balanced acrocentric rearrangements

We report the finding of paternal isodisomy for chromosome 14 in a fetus found to have a der(14;14)(q10;q10) by amniocentesis. The pregnancy was complicated by severe polyhydramnios and elevated amniotic fluid alpha-fetoprotein (AFP). The infant showed features consistent with paternal uniparental disomy (UPD) including postnatal growth retardation, poor respiratory function, feeding difficulties, and evidence of hypertrophic cardiomyopathy. The present case, in addition to other reported cases of UPD involving balanced acrocentric rearrangements, supports testing for UPD in prenatally detected Robertsonian translocations and isochromosomes. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal identification of a 45,X/46,Xder(Y) mosaicism and confirmation by high resolution cytogenetics and fluorescence in situ hybridization

A 45,X/46,Xder(Y) mosaicism detected prenatally was shown to have a rare Y inversion- duplication or Y/Y translocation which can only be identified by a combination of high resolution cytogenetics and fluorescence in situ hybridization. The present data indicate the usefulness and importance of chromosome-specific probes in the identification and characterization of chromosome rearrangements.     

Prenatal diagnosis of two rare de novo structural aberrations of the Y chromosome: cytogenetic and molecular analysis

Two rare de novo structural aberrations of the Y chromosome were detected during routine prenatal diagnosis: a satellited non-fluorescent Y chromosome (Yqs), the first de novo Yqs to be reported in a fetus, and a terminal deletion of the Y chromosome long arm del(Y)(q11). In both cases detailed cytogenetic and molecular analyses were undertaken. In the case of the Yqs it was demonstrated by fluorescence in situ hybridization (FISH) that the satellites were derived from chromosome 15. In the case of the del(Yq), it was shown with molecular analysis by polymerase chain reaction (PCR) amplification of sequence-tagged sites (STS-PCR) that the deleted portion of the long arm of chromosome Y included the azoospermia factor loci, AZFb and AZFc. The clinical significance of these findings is discussed. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of an extra der(4) resulting from a complex maternal chromosome translocation

We report the prenatal diagnosis of an extra der(4) resulting from 4:2 malsegregation of a maternal balanced complex translocation involving chromosomes 4, 10, and 11. The woman was referred for amniocentesis because of recurrent miscarriages. Fluorescence in situ hybridization was performed in order to characterize the complex chromosome rearrangement. Following genetic counselling, the couple decided to terminate the pregnancy. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p

We report the prenatal diagnosis of a fetus with sacrococcygeal teratoma and facial dysmorphism attributed to a constitutional terminal deletion of chromosome 7q and partial trisomy of chromosome 2p likely resulting from a de novo balanced translocation. The cytogenetic abnormality was diagnosed prenatally after sonographic detection of teratoma and confirmed on peripheral blood cells at birth. The newborn died of post-operative complications at seven days of age. FISH analysis demonstrated haploinsufficiency of HLXB9, a gene identified in the triad of a presacral mass (teratoma or anterior meningocele), sacral agenesis, and anorectal malformation, which constitutes the Currarino syndrome. Despite the absence of other features of the triad, the teratoma observed in the fetus we describe might represent a partial form of Currarino syndrome. Copyright © 2003 John Wiley & Sons, Ltd.     

Correlation between phenotypic expression of de novo marker chromosomes and genomic organization using replicational banding

It has been suggested that actively expressed genes are primarily located in early replicating bands. This hypothesis is supported by cytogenetic and pregnancy outcome data from four consecutive cases of prenatally detected de novo marker chromosomes. Two fetuses with major anomalies had large early replicating bands, while the marker in a third phenotypically normal fetus was late replicating. In the fourth case, a ring marker chromosome had only a small early replicating region. Pregnancy termination was elected. While no structural malformations were apparent, potential intellectual function in this case remains unresolved. An understanding of the relationship between genomic organization and chromosome banding is critical in counseling for prenatally detected de novo marker chromosomes. Replicational banding is particularly helpful in recognizing genes that may be actively expressed and result in developmental abnormality.     

Karyotypes found in the population declared at increased risk of Down syndrome following maternal serum screening

Of the 65 328 pregnancies of South Australian mothers screened by the South Australian Maternal Serum Antenatal Screening (SAMSAS) Programme between 1 January 1991 and 31 December 1997, 3431 (5.25%) were declared at increased risk of fetal Down syndrome. Fetal or neonatal karyotype was determined in 2737/3431 (79.8%) of these pregnancies, including 16 with early fetal loss. Interrogation of the database of the South Australian Neonatal Screening Service showed 643 live-born infants whose phenotype was not subsequently questioned among the 694 pregnancies whose karyotype was not determined. Of the remaining 51/3431 pregnancies, 19 ended in early fetal loss without karyotyping and no newborn screening or other records could be found for 32 cases. The 129 instances of abnormal karyotype found were Down syndrome (84), trisomy 18 (four), trisomy 13 (three), triploidy (two), female sex chromosome aneuploidy (six) and male sex chromosome aneuploidy (five), inherited balanced rearrangements (19), mosaic or de novo balanced abnormalities (four) and unbalanced karyotypes (two). In the pregnancies declared at increased risk of fetal Down syndrome, only the karyotype for Down syndrome occurred with a frequency greater than that expected for the general, pregnant population. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis in two cases of de novo complex balanced chromosomal rearrangements. Three-year follow-up in one case

We report two cases of apparently balanced complex de novo chromosomal rearrangements (BCCR) detected prenatally at 17 weeks and 10 weeks of gestation, respectively. Chromosomes were studied using GTG-banding and fluorescent in situ hybridization (FISH). In one case four chromosomes and in the other case three chromosomes were involved in the rearrangements. One of the pregnancies was terminated and no external or internal abnormalities were detected at autopsy. The other pregnancy continued to term. Level III ultrasound examination showed no abnormalities. The child is now 3 years old and has neither congenital anomalies nor evidence of delayed psychomotor development.     

Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15

We report the prenatal diagnosis of a fetus with a de novo Robertsonian translocation: 45,XY,der(15;15)(q10;q10). Although Robertsonian translocations are common chromosomal rearrangements, those involving homologous chromosomes are infrequent. Since chromosome 15 is imprinted, uniparental disomy (UPD) is a concern when chromosomal rearrangements involving chromosome 15 are identified. In the present case, UPD studies showed normal biparental inheritance. In contrast to the fact that most homologous acrocentric rearrangements are isochromosomes, these results indicate postzygotic formation of a Robertsonian translocation between biparentally inherited chromosomes 15. Copyright © 2001 John Wiley & Sons, Ltd.