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.     

Translocation Down syndrome in Ohio 1970-1981: epidemiologic and cytogenetic factors and mutation rate estimates.

Sixteen hundred eighty-eight Down syndrome live births, including 65 (5.2%) translocations, were ascertained in Ohio between 1970 and 1981. Translocations of known origin were 24.4% maternal, 2.2% paternal, and 73.3% de novo. Translocation subtypes were 14/21 (45.7%), 15/21 (2.9%), 21/21 (40.0%), 21/22 (2.9%), and other (8.5%). Among 14/21 translocations, 33.3% were maternal in origin and 66.7% were de novo, while 100% of 21/21 translocations were de novo. No differences were found when the maternal- and paternal-age distributions of all translocations or various translocation subsets were compared with the live-birth control distributions. However, mean maternal and paternal ages of de novo translocations were significantly lower than that of the live-birth controls. Ohio data showed the average maternal age of de novo D/21 cases to be significantly lower than the control. Ages of both parents of de novo G/21 cases and paternal age of D/21 cases were not different from the control. De novo translocation mutation rate estimates were 0.8 X 10(-5) for 14/21, 1.2 X 10(-5) for 21/21, and 2.2 X 10(-5) overall. Ohio estimates (3.2 X 10(-5) for 1970-1972 and 1.4 X 10(-5) for 1973-1975) did not reflect the increase in mutation rate previously found in New York during 1973-1977.     

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.     

Parental origin of de novo constitutional deletions of chromosomal band 11p13.

One-half of all cases of Wilms tumor (WT), a childhood kidney tumor, show loss of heterozygosity at chromosomal band 11p13 loci, suggesting that mutation of one allele and subsequent mutation or loss of the homologous allele are important events in the development of these tumors. The previously reported nonrandom loss of maternal alleles in these tumors implied that the primary mutation occurred on the paternally derived chromosome and that it was "unmasked" by loss of the normal maternal allele. This, in turn, suggests that the paternally derived allele is more mutable than the maternal one. To investigate whether germinal mutations are seen with equal frequency in maternally versus paternally inherited chromosomes, we determined the parental origin of the de novo germinal 11p13 deletions in eight children by typing lymphocyte DNA from these children and from their parents for 11p13 RFLPs. In seven of the eight cases, the de novo deletion was of paternal origin. The one case of maternal origin was unremarkable in terms of the size or extent of the 11p13 deletion, and the child did develop WT. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general preponderance of paternally derived, de novo mutations at other loci, suggest that the increased frequency of paternal deletions we observed is due to an increased germinal mutation rate in males.     

Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors

Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥ 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥ 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.     

Rates of mutant structural chromosome rearrangements in human fetuses: data from prenatal cytogenetic studies and associations with maternal age and parental mutagen exposure.

In 27,225 prenatal cytogenetic studies of amniotic fluid reported to the New York State Chromosome Registry and the United States Interregional Chromosome Register System, there were 61 cases with a structural chromosomal abnormality not known inherited, a rate per 1,000 of 2.24. Of these 33, 1.21 per 1,000 were known de novo and nonmosaic; consequently, the rate of events resulting from germinal mutation is highly likely to be between these two limits. The rates per 1,000 of unbalanced abnormalities were 0.59-1.29; of balanced abnormalities, 0.62-0.96; of balanced Robertsonian translocations, 0.22-0.29; and of unbalanced Robertsonian translocations, 0.07-0.11. The rates of fetuses with supernumerary markers and fragments were unexpectedly high: 0.26-0.70 per 1,000. These abnormalities were associated with increased maternal age (38.0 +/- 5.4 to 38.4 +/- 3.6 compared to 35.6 +/- 4.3 in controls), but even after adjustment for the bias to preferential study of older women, the observed rates of these supernumerary abnormalities were greater than would be expected from live-birth studies or rates estimated in all recognized conceptuses. There were trends to elevated maternal age for the group of all balanced rearrangements, and to diminished maternal age for the nonsupernumerary, non-Robertsonian unbalanced rearrangements. In 136 women studied primarily because of exposure to a putative mutagen, a de novo deletion and an inversion not known inherited were detected. The rate of abnormality in these 136, 1.47%, was significantly greater than the rate of abnormality in the remainder: 0.14%-0.22%.     

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.     

A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange.     

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.     

MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P<.001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female:male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.     

Results of estimation of mutation rates for translocation trisomy 21

Among 1332 cases of trisomy 21 born within 1979-1999 in St. Petersburg, 76(5.7%) were carriers of a translocation between chromosome 21 and other acrocentrics. Among 43 Dq; 21q translocations, 17 were inherited from the mother, and one was inherited from the father, 16 were of sporadic occurrence, and in 9 cases the mode of inheritance was not established. Out of 31 cases displaying Gq;21 translocation, 23 were mutants and 8 of unknown origin. One case of non-Robertsonian translocation 21;22 was maternal in origin. It was assumed that the proportion of sporadic cases among translocations of unknown origin is the same as that among translocations of the known origin. However, it is conceivable that the parents of a child with a sporadic anomaly, previously having an uncomplicated reproductive history and healthy children, tend to avoid cytogenetic examination more often than the carriers of translocation. Hence, the reported proportion of de novo cases (-0.6) might be underestimated. The analysis of pregnancy outcomes in mothers of children with Down syndrome, who inherited translocation (n = 12), sporadic translocation (n = 12) and translocation of unknown origin (n = 8), supports this suggestion. Analysis of the data from 8 reports, where the origin of Dq;21 was specified, revealed that in those samples, where the origin was traced in almost all families, the proportion of de novo cases (0.75-0.82) was higher than in samples where an appreciable part of families was not examined (0.46-0.73). Therefore, with the aim of correct determination of mutation rate for Dq;21 translocation, the true proportions in D;21 cases merit evaluation. Meanwhile, using average estimation from all the above mentioned reports (0.67), the mutation rate for translocations Dq;21 in St. Petersburg was calculated to be 1.2 x 10(-5) and 0.8 x 10(-5) in 1980-1989 and 1990-1999, respectively. For Gq;21 translocations/isochromosomes, the corresponding figures were 1.6 x 10(-5) and 1.5 x 10(-5).     

Parental origin of germ-line and somatic mutations in the retinoblastoma gene

Segregation analysis of polymorphic sites within the retinoblastoma (RB) gene and on chromosome 13, as well as the parental origin of the lost allele in the tumor, were analyzed in 24 families with RB patients. Four mutant alleles transmitted through the germ-line and seven de novo germ-line mutant alleles were identified in 11 patients with hereditary RB. Segregation analysis within the RB gene and on chromosome 13 was useful for DNA diagnosis of susceptibility to RB in relatives of hereditary patients, even if mutations were not identified. All seven de novo germ-line mutant alleles were paternally derived. The bias toward the paternal allele for de novo germ-line mutations of the RB gene was statistically significant. Seven paternal alleles and six maternal alleles were lost in 13 non-hereditary RB tumors with no bias in the parental origin of the somatic allele loss. These results suggest that the physical environment or a deficiency in DNA repair during spermatogenesis may be associated with significant risk factors for de novo germ-line mutations.     

Disease associated balanced chromosome rearrangements (DBCR): report of two new cases

Disease associated balanced chromosome rearrangements (DBCR) causing truncation, deletion, inactivation or over-expression of specific genes are instrumental in identifying and cloning several disease genes and are estimated to be much more common than anticipated. In one survey, the minimal frequency of combined balanced de novo reciprocal translocations and inversions causing abnormal phenotype is estimated to be 0.17%, a sixfold increase compared to the general population suggesting a causative linkage between the abnormality and the observed phenotypic traits. Here, we report two new cases of apparently balanced de novo translocations resulting in developmental delay and dysmorphic features.     

Prevalence and origin of de novo duplications in Charcot-Marie-Tooth disease type 1A: first report of a de novo duplication with a maternal origin.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that > or = 10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus.     

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.     

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.     

Unexpected Inheritance of a Balanced Homologous translocation t(22q;22q) from father to a phenotypically normal daughter

Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of balanced homologous chromosomal translocation t (22q; 22q) and only two cases of transmission of this balanced homohologous rearrangement from mother to normal daughter are reported. Robersonian translocation carriers in non-homologous chromosomes have the ability to have an unaffected child. However, it is not possible to have an unaffected child in cases with Robersonian translocations in homologous chromosomes. Carriers of homologous chromosome 22 translocations with maternal uniparental disomy do not have any impact on their phenotype. We are presenting a family with a history of multiple first trimester miscarriages and an unexpected inheritance of balanced homologous translocation of chromosome 22 with paternal uniparental disomy. There are no data available regarding the impact of paternal UPD 22 on the phenotype. We claim this to be the first report explaining that paternal UPD 22 does not impact the phenotype.     

Excess of mental retardation and/or congenital malformation in reciprocal translocations in man

Summary In this report the Leuven experience (1970–1984) on reciprocal translocations is summarized. A total of 153 unrelated index patients, carriers of different types of reciprocal translocations, and their families were investigated. Familial reciprocal, apparently balanced translocations were found in 75 unrelated families bringing the total numbers of translocation carrier parents and their offspring to 132 and 445, respectively. In 61.5% of the patients the reciprocal translocation was detected after the birth of a malformed child with unbalanced karyotype or through investigation because of recurrent spontaneous abortions, stillbirths, or infertility. In 41 patients (28 familial and 13 de novo), however, the reciprocal balanced translocation was found to be associated with mental retardation and/or congenital malformations (MR/CM) which is significantly higher than expected. This excess of MR/CM in de novo and familial balanced translocation carriers is illustrated and discussed.     

Wolf–Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16

The basic genomic defect in Wolf–Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Web Resources: Electronic Database Information: Online Mendelian Inheritance in Man (OMIM), (for WHS [MIM 194190]; Ensembl Human Map, ; UCSC, . An erratum to this article can be found at     

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.