Inherited structural cytogenetic abnormalities detected incidentally in fetuses diagnosed prenatally: frequency, parental-age associations, sex-ratio trends, and comparisons with rates of mutants

Rates of structural chromosome abnormalities were analyzed in 24,951 fetuses studied prenatally in which there were no grounds to suspect an inherited abnormality. In about one in 200 prenatal cytogenetic diagnoses, an unexpected structural abnormality was found. The observed rate was 5.3 per 1,000, of which 1.7 per 1,000 were unbalanced and 3.6 per 1,000 balanced. The rate of inherited abnormalities was 3.1-3.7 per 1,000 (0.4-0.9 per 1,000 for unbalanced abnormalities and 2.6-2.8 per 1,000 for balanced abnormalities). The rate of mutants in this series was, by contrast, 1.6-2.2 per 1,000 (0.8-1.2 per 1,000 for unbalanced abnormalities and 0.8-1.0 per 1,000 for balanced abnormalities). The rate of balanced Robertsonian translocation carriers was 0.6 per 1,000 (about 0.25 per 1,000 for mutants and 0.35 per 1,000 for inherited abnormalities), and for other balanced abnormalities, 3.0 per 1,000 (about 0.6 per 1,000 for mutants and 2.4 per 1,000 for inherited abnormalities). The rates of unbalanced Robertsonian translocations was about 0.1 per 1,000, almost all of which were mutants. For supernumerary rearrangements, the rate was 0.9 per 1,000 (about 0.4 per 1,000 inherited and 0.5 per 1,000 mutant). The rates of all unbalanced (nonmosaic) inherited abnormalities (4.0-5.2 per 10,000) were intermediate between higher rates estimated in all conceptuses (9.1-15.8 per 10,000) and rates observed in newborns (1.5-2.5 per 10,000). This trend is probably attributable to fetal mortality associated with unbalanced rearrangements. The rates of balanced (nonmosaic) inherited abnormalities (26.0-28.0 per 10,000), however, were considerably higher than the rates in all conceptuses (13-16.7 per 10,000) or in all live births (12.2-16.0 per 10,000). The major difference was in the rate of inversions. The use of "banding" methods in the studies of amniocentesis but not in most of the live births or abortus studies probably contributes to at least some of these differences. One trend in parental age among the inherited abnormalities was noteworthy. Paternal age was elevated for inherited balanced reciprocal structural abnormalities of paternal origin but not of maternal origin. With regard to sex ratio, there was a greater proportion of females than males among the unbalanced rearrangements both inherited and mutant. There was no obvious sex difference among the balanced rearrangements.     

The frequency and mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age.

The frequencies of balanced chromosome rearrangements were estimated from three series of advanced maternal-age prenatal genetic studies, and were compared to the frequencies that had been estimated from consecutive newborn surveys. In the maternal-age prenatal studies, the frequencies were: Robertsonian translocations, 0.11%; reciprocal translocations, 0.17%; and inversions, 0.12%. The total frequency of balanced rearrangements in the prenatal genetic studies performed with banding (0.40%, or 1 in 250) was twice that in the consecutive newborn surveys performed without banding (0.19%, or 1 in 526). The difference was limited to inversions and reciprocal translocations; the frequency of Robertsonian translocations was similar in the prenatal series and the newborn surveys. Both familial and de novo rearrangements were more common than anticipated. The de novo cases provided a mutation rate estimate of 4.3 per 10,000 gametes per generation (compared with 1.78 to 2.2 per 10,000 gametes in other surveys). These higher estimates may more reliably approximate the true mutation rate and frequencies of balanced rearrangements in the newborn population than do the newborn surveys.     

Mutation rates of structural chromosome rearrangements in man.

The gametic mutation rates of human structural chromosome rearrangements have been estimated from rearrangements ascertained from systematic surveys of live births and spontaneous abortions. The mutation rates for rearrangements that survive long enough to give rise to clinically recognized pregnancies are 2.20 X 10(-4) for balanced rearrangements, 3.54 X 10(-4) for unbalanced Robertsonian translocations, and 3.42 X 10(-4) for unbalanced non-Robertsonian rearrangements. These estimates give a mutation rate for all detectable structural chromosome rearrangements of approximately 1 X 10(-3). The most common single rearrangement, the Robertsonian translocation involving chromosomes 13 and 14, has a mutation rate of 1.5 X 10(-4).     

De novo microdeletion on an inherited Robertsonian translocation chromosome: a cause for dysmorphism in the apparently balanced translocation carrier.

Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangements are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogenetic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion.     

De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints.

A questionnaire sent to major cytogenetics laboratories in the United States and Canada over a 10-year period collected data on the frequency and outcome of cases with either apparently balanced de novo rearrangements or de novo supernumerary marker chromosomes detected at amniocentesis. Of 377,357 reported amniocenteses, approximately 1/2,000 had a de novo reciprocal translocation, 1/9,000 a Robertsonian translocation, 1/10,000 a de novo inversion, and 1/2,500 an extra structurally abnormal chromosome of unidentifiable origin. The risk of a serious congenital anomaly was estimated to be 6.1% (n = 163) for de novo reciprocal translocations, 3.7% (n = 51) for Robertsonian translocations, and 9.4% (n = 32) for inversions. The combined risk for reciprocal translocations and inversions was 6.7% (95% confidence limits 3.1%-10.3%). The risk of abnormality for extra nonsatellited marker chromosomes was 14.7% (n = 68), and that for satellited marker chromosomes was 10.9% (n = 55). In non-Robertsonian rearrangements, distribution of breakpoints among chromosomes was not as would be expected strictly on the basis of length. Most breaks were stated to occur within G-negative bands, but there was little evidence of particular hot spots among these bands. Nevertheless, there did appear to be a correlation between those bands in which breakage was observed most often and those bands where common or rare fragile sites have been described.     

Balanced chromosome rearrangements with abnormal phenotype

27 cases in which apparent balanced chromosomal rearrangements (reciprocal and translocations and pericentric inversions) are associated with phenotypic abnormalities are reported and compared with the previous published cases. Almost all patients display mental retardation and a non specific dysmorphism. Genetic counseling is different whether the abnormality is inherited or de novo. When an unexpected structural rearrangements is found in fetal cells, the attitude depends on the results of the parent's chromosomal study.     

Patterns of chromosomal translocations identified by a birth defects registry, Hawaii, 1986-2000

Using a birth defects registry, this investigation examined the distribution of translocations by type of translocation, chromosomes involved in the translocation, pregnancy outcome, method of diagnosis, inheritance, and diagnosis of major structural birth defects. A total of 121 cases were identified through a statewide population-based birth defects registry. The translocations were reciprocal in 89 (73.6%) cases, Robertsonian in 32 (26.4%) cases, balanced in 86 (71.1%) cases, and unbalanced in 35 (28.9%) cases. Live births accounted for 76 (88.4%) of balanced translocations and 22 (62.9%) of unbalanced translocations. Diagnosis was made by amniocentesis or chorionic villus sampling in 72 (83.7%) of balanced translocations and 11 (31.4%) of unbalanced translocations. Of cases of known inheritance, the translocation was of maternal origin in 38 (46.3%) cases, paternal origin in 25 (30.5%) cases, and de novo in 19 (23.2%) cases. Major structural birth defects were diagnosed in 17 (19.8%) of balanced translocations and 20 (57.1%) of unbalanced translocations. Translocations were more likely to be reciprocal, balanced, and of maternal origin. Infants and fetuses with unbalanced translocations were less likely to be live births and diagnosed by amniocentesis or chorionic villus sampling and more likely to be diagnosed with major structural birth defects.     

Extra structurally abnormal chromosomes (ESAC) detected at amniocentesis: frequency in approximately 75,000 prenatal cytogenetic diagnoses and associations with maternal and paternal age.

We analyzed rates of extra structurally abnormal chromosomes (ESAC) detected in prenatal cytogenetic diagnoses of amniotic fluid reported to the New York Chromosome Registry. These karyotypes include both extra unidentified structurally abnormal chromosomes (EUSAC)--often denoted as "markers"--and extra identified structurally abnormal chromosomes (EISAC). The rate of all EUSAC was 0.64/1,000 (0.32-0.40/1,000 mutant and 0.23-0.32 inherited), and that of all EISAC was 0.11/1,000 (0.07/1,000 mutant and 0.04/1,000 inherited). The rate of all ESAC was approximately 0.8/1,000-0.4-0.5/1,000 mutant and 0.3-0.4/1,000 inherited. Mean +/- SD maternal age of mutant cases was 37.5 +/- 2.9, significantly greater than the value of 35.8 years in controls. A regression analysis indicated a rate of change of the log of the rate of about +0.20 with each year of maternal age between 30 and 45 years. When paternal age was introduced, the maternal age coefficient increased to about +0.25--close to that seen for 47, +21--but the paternal age coefficient was -0.06. After being matched for maternal age and year of diagnosis, the case-control difference in paternal age for 24 mutant cases was -2.4 with a 95% confidence interval of -4.6 to -0.1 years. In a regression analysis of the effects of both parental ages on the (log) rate, the maternal age coefficient was +0.25 and the paternal age coefficient was -0.06. These results are consistent with a (weak) negative paternal age effect in the face of a strong maternal age effect. Since ESAC include a heterogeneous group of abnormalities, the maternal age and paternal age trends, if not the result of statistical fluctuation or undetected biases, may involve different types of events. Data in the literature suggest that chromosomes with de novo duplicated inversions of 15p have a strong maternal age effect (but little paternal age effect). Such chromosomes, however, do not account for the active maternal age trends seen in the data analyzed here. Inherited ESAC exhibited no such trends.     

Two novel reciprocal translocations involving chromosome 6 in the domestic pig]

In the present study 2 new reciprocal translocations are described in two hypoprolific boars. The first one, a Gascon/Meishan boar, has produced a mean value of 7.37 +/- 0.69 piglets, vs 12.41 +/- 0.22 piglets per litter in contemporaries. The second one, a Pietrain/Large-White boar, has produced a mean of 5.42 +/- 0.69 vs 12.41 +/- 0.22 piglets per litter in contemporaries. Each of these animals carries a new chromosome translocation involving chromosomes 6, 8 and 15, respectively. The first translocation seems to be a de novo occurring abnormality. The economic consequences of these abnormalities are discussed. Carrier of the gene HAL, the abnormal chromosomes 6 involved in these translocations are important, and could useful markers in gene mapping and flow cytometry studies in pigs.     

Mental retardation associated with "balanced" chromosome rearrangements.

Balanced chromosome rearrangements were found in seven of 455 retarded children vs. four of 1,679 nonretarded, psychiatric children (P less than .05). The combined incidence of non-Robertsonian balanced rearrangements from this and reported surveys of the mentally retarded was five times greater than that from newborn surveys, whereas Robertsonian translocations were not increased among the retarded. The combined data show an increase in de novo rather than familial rearrangements among the retarded; the increase in de novo rearrangements is specifically for non-Robertsonian translocation.     

Parental and chromosomal origin of unbalanced de novo structural chromosome abnormalities in man

We report the parental origin, and where possible the chromosomal origin of 115 de novo unbalanced structural chromosome abnormalities detectable by light microscopy. These consisted of 39 terminal deletions, 35 interstitial deletions, 8 rings, 12 duplications and 21 unbalanced translocations. In all categories the majority of abnormalities were of paternal origin, although the proportions varied from a high of 84% in the interstitial deletions and rings to a low of 58% in the duplications. Among the interstitial deletions and duplications, there were approximately equal numbers of intra- and interchromosomal abnormalities, while the majority of unbalanced translocations were isodisomic for the duplicated chromosome. The examination of the parental ages in the four main classes of abnormality showed terminal deletions of maternal origin to be associated with a significantly reduced maternal age. Thus, there is a clear propensity for structural chromosome abnormalities to occur in male germ cells, although the chromosomal origin seems similar irrespective of the parental origin.     

Unusual supernumerary chromosomes: types encountered in a referred population,and high incidence of associated maternal chromosome abnormalities

Summary In a 6-year period 128 patients with supernumerary autosomes were identified in our laboratory. The majority had primary trisomy, but 19 (15%) had extra, unusual chromosomes, not just a normal chromosome present in an extra copy. Of these, 18 were complex and did not resemble any one part of the standard chromosome complement. There was a preponderance of females among the 19 cases. Chromosome analysis of the parents in the 14 most recent cases revealed maternal chromosome abnormalities in 11 (79%). Of these 11, eight mothers had balanced reciprocal translocations; nondisjunction led to the smaller of their translocation chromosomes being passed on as the supernumerary chromosome in their offspring. Thus, nondisjunction of maternal translocations accounts for a major proportion of the unusual supernumerary chromosomes found by our laboratory. Advanced maternal age was noted in this group of mothers. Three mothers had supernumerary chromosomes themselves. We conclude that unusual supernumerary chromosomes (1) are not rare among patients referred for chromosome studies; (2) are generally not simple products of breakage; (3) are very frequently the result of malsegregation of a balanced maternal reciprocal translocation; and (4) are very difficult to characterize unless a balanced parental translocation is identified. Parental karyotypes should be obtained whenever a patient has an extra, unusual chromosome.     

Analysis of translocations observed in three different populations. II. Robertsonian translocations

A sample of 229 Robertsonian translocations was classified into three groups according to the method of their ascertainment (Group I = couples with repeated abortions; Group II = karyotypically unbalanced probands; Group III = balanced translocation heterozygotes). Statistical analysis showed that the distributions of Robertsonian translocations differed significantly from random in all three groups. Additionally, the distributions were significantly different between couples with repeated abortions and karyotypically unbalanced probands and between unbalanced probands and balanced translocation heterozygotes.     

Gamete segregation in female carriers of Robertsonian translocations

Eleven female carriers of either 45,XX,der(13;14) (q10;q10) or 45,XX, der(14;21)(q10;q10) underwent hormonal stimulation with the purpose of producing enough oocytes for in-vitro fertilization and preimplantation genetic diagnosis. Polar body biopsy was performed in those oocytes and FISH with painting probes was applied in their metaphase-like first polar body chromosomes. In this way, unbalanced, normal and balanced oocytes could be distinguished and segregation modes ascertained. der(14;21)(q10;q10) produced 42% unbalanced, 37% normal and 21% balanced oocytes (n = 86) while der(13;14)(q10;q10) generated 33% unbalanced, 51% normal and 16% balanced oocytes (n = 69). In both translocations the number of normal oocytes was significantly higher than the number of balanced oocytes. However, while the frequency of unbalanced events involving chromosome 13 and 14 was similar in der(13;14)(q10;q10), there were significantly more abnormalities involving chromosome 21 than 14 in the der(14;21) (q10;q10) cases. When comparing survival rates to term, trisomies from Robertsonian origin seem to survive more often than those originated by non-disjunction in non-translocation carriers. The meiotic segregation patterns found in female Robertsonian translocations are different from those described in male carriers, with higher rates of unbalanced gametes in females than in males.     

Cryptic Subtelomeric Rearrangements and X Chromosome Mosaicism: A Study of 565 Apparently Normal Individuals with Fluorescent In Situ Hybridization

Five percent of patients with unexplained mental retardation have been attributed to cryptic unbalanced subtelomeric rearrangements. Half of these affected individuals have inherited the rearrangement from a parent who is a carrier for a balanced translocation. However, the frequency of carriers for cryptic balanced translocations is unknown. To determine this frequency, 565 phenotypically normal unrelated individuals were examined for balanced subtelomeric rearrangements using Fluorescent In Situ hybridization (FISH) probes for all subtelomere regions. While no balanced subtelomeric rearrangements were identified, three females in this study were determined to be mosaic for the X chromosome. Mosaicism for XXX cell lines were observed in the lymphocyte cultures of 3 in 379 women (0.8%), which is a higher frequency than the 1 in 1000 (0.1%) reported for sex chromosome aneuploidies. Our findings suggest that numerical abnormalities of the X chromosome are more common in females than previously reported. Based on a review of the literature, the incidence of cryptic translocation carriers is estimated to be approximately 1/8,000, more than ten-fold higher than the frequency of visible reciprocal translocations.     

High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome.

The application of fluorescence in situ hybridization (FISH) using whole-chromosome paints (WCPs) is proving to be a very powerful technique for revealing chromosomal instability that, for the most part, has gone undetected by conventional cytogenetic analysis. We have analyzed the frequency of translocations in lymphocytes and lymphoblastoid cell lines from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) homozygotes and heterozygotes using a three-color chromosome-painting technique (WCP 1, 2, 4). With this assay we were able to detect an increased frequency of spontaneous translocations in AT homozygotes (median, 18.47 +/- 10.82 translocations per 1,000 metaphase cells; 10 patients) and AT heterozygotes (median, 7.87 +/- 3.15 translocations per 1,000 cells; 7 patients), in comparison to controls (median, 2.26 +/- 1.75 translocations per 1,000 cells; 10 controls). Analysis of NBS homozygotes (median, 19.05 +/- 11.27 translocations per 1,000 cells; 5 patients) and NBS heterozygotes (median, 6.93 +/- 3.04 translocations per 1,000 cells; 6 patients) also showed an increased frequency of translocations in these patients compared to controls. The presence of such hitherto undetected chromosomal aberrations corroborate previous findings of spontaneous chromosomal instability in AT and NBS patients, as manifested by an increased rate of open breaks and rearrangements involving chromosomes 7 and 14. Moreover, we show that the degree of genomic instability in AT and NBS patients is even higher than previously established and that some AT and NBS heterozygotes evidence spontaneous chromosomal instability as well. These increased levels of nonspecific translocations could be an important risk factor for the development of malignancies in homozygotes and heterozygotes for ATM or NBS1 gene mutations.     

Chromosomal abnormalities in the Kaiser-Permanente Birth Defects Study, with special reference to contraceptive use around the time of conception

Chromosomal abnormalities were studied in 33,551 abortions and births to women whose contraceptive histories had been recorded at their first antenatal visit in 1975-1977. Chromosome examinations were performed exclusively on clinical grounds. There were 45 de novo abnormalities detected (1.34/1,000); three of them were detected at amniocentesis. Trisomy 21 was observed in 27 cases (0.80/1,000), trisomy 18 in nine (0.27), other trisomies in three (0.09), and translocations or deletions in five (0.15). One case of triploidy and six cases of inherited abnormalities were detected. There were no significant racial variations. No increase in risk for chromosomal abnormalities was found among women who had used oral contraceptives prior to becoming pregnant or among women who experienced oral contraceptive breakthrough pregnancies. Two cases of trisomy 18 were observed among the 814 deliveries following oral contraceptive breakthrough conceptions (2.46/1,000), two cases of trisomy 21 occurred in 338 births following failures of rhythm contraception (5.92/1,000), and no cases of trisomy 21 or 18 among the 1,569 women using spermicides at the time of conception.     

Molecular characterization of de novo secondary trisomy 13.

Unbalanced Robertsonian translocations are a significant cause of mental retardation and fetal wastage. The majority of homologous rearrangements of chromosome 21 in Down syndrome have been shown to be isochromosomes. Aside from chromosome 21, very little is known about other acrocentric homologous rearrangements. In this study, four cases of de novo secondary trisomy 13 are presented. FISH using alpha-satellite sequences, rDNA, and a pTRI-6 satellite I sequence specific to the short arm of chromosome 13 showed all four rearrangements to be dicentric and apparently devoid of ribosomal genes. Three of four rearrangements retained the pTRI-6 satellite I sequence. Case 1 was the exception, showing a deletion of this sequence in the rearrangement, although both parental chromosomes 13 had strong positive hybridization signals. Eleven microsatellite markers from chromosome 13 were also used to characterize the rearrangements. Of the four possible outcomes, one maternal Robertsonian translocation, two paternal isochromosomes, and one maternal isochromosome were observed. A double recombination was observed in the maternally derived rob(13q13q). No recombination events were detected in any isochromosome. The parental origins and molecular chromosomal structure of these cases are compared with previous studies of de novo acrocentric rearrangements.     

Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations

Robertsonian translocations are the most common structural rearrangements of human chromosomes. Although segregation of Robertsonian chromosomes has been examined in many families, there is little consensus on whether inheritance in the balanced progeny conforms to Mendelian ratios. To address this question, we have compiled previously reported segregation data, by sex of parent, for 677 balanced offspring of Robertsonian carriers from 82 informative families and from a prenatal diagnosis study on the risk of unbalanced offspring in carriers of chromosome rearrangements. Care was taken to avoid any source of ascertainment bias. Our analysis supports the following conclusions: (1) the transmission ratio is not independent of the sex of the carrier; (2) the transmission ratio distortion is observed consistently only among the offspring of carrier females; (3) the transmission ratio distortion does not appear to be dependent on the presence of a specific acrocentric chromosome in the rearrangement. The sex-of-parent-specific origin of the non-Mendelian inheritance, the finding that the rearranged ("mutant") chromosomes are recovered at significantly higher frequency than the acrocentric ("normal") chromosomes, and the similarities between these observations and the segregation of analogous rearrangements through female meiosis in other vertebrates strongly support the hypothesis that the transmission ratio distortion in favor of Robertsonian translocations in the human results from the preferential segregation of chromosomes during the first meiotic division. This non-Mendelian inheritance will result in increased overall risk of aneuploidies in the families of Robertsonian translocation carriers, independently of the origin of the transmission ratio distortion.     

Robertsonian Translocations: An Overview of 872 Robertsonian Translocations Identified in a Diagnostic Laboratory in China

Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population.