Nonreciprocal and jumping translocations of 15q1----qter in Prader-Willi syndrome

We analyzed 33 cases of Prader-Willi syndrome (PWS) (including 2 personal observations) with translocations of 15q1----qter onto the terminals of different, apparently whole chromosomes. In all but one of the 23 informative cases the translocations was de novo. Thirty of the patients were unbalanced and 27 had a 45-chromosome constitution compatible with a 3:1 segregation. One balanced and 2 unbalanced translocations were jumping ones. The possible existence of actual non-reciprocal translocations in man is indicated by the following considerations about these and other PWS-associated rearrangements: 1) The observed excess of de novo translocations; 2) the relatively frequent familial occurrence of reciprocal 15q translocations; 3) the concurrence in 3 terminal translocation cases of an idic (15); 4) the visualization of jumping terminal translocations as simple transpositions rather than as successive reciprocal exchanges; 5) the predominance of true isodicentrics in PWS patients with extra inv dup(15) chromosomes; and 6) the rarity of extra derivatives resulting in 15q proximal tertiary trisomy. Additional findings in the present series were normal parental age in the de novo 45-chromosome cases, an apparently random distribution of telomeric breakpoints, and the occurrence of different breakpoints within the 15q1 region.     

Translocations in Prader-WiIIi syndrome

The Prader-Willi Syndrome (PWS) has frequently been associated with chromosomal anomalies involving the region 15q11-q12. The first case of this syndrome associated with a de novo translocation involving chromosomes 11 and 15 is reported. The breakpoints were identified as 11q25 and 15q11 or q12[45, XX,t(11;15)(q25;q11-12)], resulting in the deletion of 15pter leads to 15q11-q12. Previously reported cases of PWS associated with translocations are reviewed in relation to the "deletion hypothesis."     

Prader-Willi syndrome resulting from an unbalanced translocation: characterization by array comparative genomic hybridization

Prader-Willi syndrome (PWS) is caused by lack of expression of paternally inherited genes on chromosome 15q11-->15q13. Most cases result from microdeletions in proximal chromosome 15q. The remainder results from maternal uniparental disomy of chromosome 15, imprinting center defects, and rarely from balanced or unbalanced chromosome rearrangements involving chromosome 15. We report a patient with multiple congenital anomalies, including craniofacial dysmorphology, microcephaly, bilateral cryptorchidism, and developmental delay. Cytogenetic analysis showed a de novo 45,XY,der(5)t(5;15)(p15.2;q13), -15 karyotype. In effect, the proband had monosomies of 5p15.2-->pter and 15pter-->15q13. Methylation polymerase chain reaction analysis of the promoter region of the SNRPN gene showed only the maternal allele, consistent with the PWS phenotype. The proband's expanded phenotype was similar to other patients who have PWS as a result of unbalanced translocations and likely reflects the contribution of the associated monosomy. Array comparative genomic hybridization (array CGH) confirmed deletions of both distal 5p and proximal 15q and provided more accurate information as to the size of the deletions and the molecular breakpoints. This case illustrates the utility of array CGH in characterizing complex constitutional structural chromosome abnormalities at the molecular level.     

Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms

Jumping translocations (JTs) and segmental jumping translocations (SJTs) are unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to multiple recipient chromosomes. In leukemia, where JTs have been predominantly observed, the donor segment (usually 1q) preferentially fuses to the telomere regions of recipient chromosomes. In this study, spectral karyotyping (SKY) and FISH analysis revealed 188 JTs and SJTs in 10 cell lines derived from carcinomas of the bladder, prostate, breast, cervix, and pancreas. Multiple JTs and SJTs were detected in each cell line and contributed to recurrent unbalanced whole-arm translocations involving chromosome arms 5p, 14q, 15q, 20q, and 21q. Sixty percent (113/188) of JT breakpoints occurred within centromere or pericentromeric regions of the recipient chromosomes, whereas only 12% of the breakpoints were located in the telomere regions. JT breakpoints of both donor and recipient chromosomes coincided with numerous fragile sites as well as viral integration sites for human DNA viruses. The JTs within each tumor cell line promoted clonal progression, leading to the acquisition of extra copies of the donated chromosome segments that often contained oncogenes (MYC, ABL, HER2/NEU, etc.), consequently resulting in tumor-specific genomic imbalances. Published 2001 Wiley-Liss, Inc.     

A translocation breakpoint cluster disrupts the newly defined 3' end of the SNURF-SNRPN transcription unit on chromosome 15

Balanced translocations affecting the paternal copy of 15q11--q13 are a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Here we report on the cytogenetic and molecular characterization of a de novo balanced reciprocal translocation t(X;15)(q28;q12) in a female patient with atypical PWS. The translocation breakpoints in this patient and two previously reported patients map 70-80 kb distal to the SNURF-SNRPN gene and define a breakpoint cluster region. The breakpoints disrupt one of several hitherto unknown 3' exons of this gene. Using RT--PCR we demonstrate that sequences distal to the breakpoint, including the recently identified C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 as well as IPW and PAR1, are not expressed in the patient. Our data suggest that lack of expression of these sequences contributes to the PWS phenotype.     

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.     

A constitutional telomeric translocation showing meiotic instability

Constitutional telomeric translocations are rare chromosome rearrangements. They are thought to occur as a result of chromosome breakage and subsequent ligation with the telomeric sequence of a different chromosome. Most frequently they occur as de novo events and, depending on the donor chromosome breakpoint, may be associated with an abnormal phenotype. We report a case of an unbalanced translocation involving the long arm of chromosome 15 and the short arm of chromosome 8 [45,XY, der(8)t(8;15)(p23.3;q11.2),-15], diagnosed prenatally; the father carried an unbalanced translocation of the long arm of chromosome 15 and the short arm of chromosome 2 [45,XY,der(2)t(2;15)(p25.3;q11.2),-15]. Both translocations were shown to have telomere repeat sequences at the translocation breakpoints. There was no apparent imbalance of euchromatic material in either translocation, and no associated abnormal phenotype.     

Molecular studies of translocations and trisomy involving chromosome 13

Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo dic(13,13) (p12p12) chromosome, were examined with molecular markers to determine the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative patients were consistent with a maternal origin of the extra chromosome. Lack of a third allele at any locus in both paternal origin cases indicate a somatic duplication of the paternal chromosome occurred. Five cases had translocation trisomy: one de novo rob(13q14q), one paternally derived rob(13q14q), two de novo t(13q13q), and one mosaic de novo t(13q13q)/r(13). The patient with a paternal rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13q14q) carrier and most trisomies are maternal in origin, this result should not be surprising; however, it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. Lack of a third allele at any locus in one of the three t(13q13q) cases indicates that it was most likely an isochromosome of postmeiotic origin, whereas the other two cases showed evidence of recombination. One balanced (nontrisomic) case with a nonmosaic 45,−13,−13,t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologues, as has been found for all balanced homologous Robertsonian translocations so far investigated. Thus, it is also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. Despite a maternal origin of the trisomy, we cannot therefore infer anything about the parental origin of the chromosomes 13 and 14 involved in the translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes showing a meiotic origin of the trisomy. © 1996 Wiley-Liss, Inc.     

Prenatal diagnosis and characterization of an unbalanced whole arm translocation resulting in monosomy for 18p

Monosomy for the short arm of chromosome 18 is one of the most frequent autosomal deletions observed. While most cases result from terminal deletion of 18p, 16% of cases reported were as a result of an unbalanced whole arm translocation resulting in monosomy 18p. The origin and structure of these derivative chromosomes were reported in only a few cases. We report the prenatal diagnosis and characterization of a new case of monosomy 18p as a result of an unbalanced whole arm translocation. Amniocentesis was performed at 15 weeks of gestation on a 34-year-old woman initially referred for advanced maternal age. Holoprosencephaly was identified by ultrasound at the time of amniocentesis. Karyotype analysis showed an unbalanced whole arm translocation between the long arm of one chromosome 18 and the long arm of one chromosome 22, 45,XX,der(18;22)(q10;q10), in all metaphases. In effect, the fetus had monosomy for 18p. Parental karyotypes were normal, suggesting a de novo origin for the der(18;22). Fluorescence in situ hybridization (FISH) analysis was performed with alpha-satellite probes D18Z1 and D14Z1/D22Z1 to identify the origin of the centromere on the der(18;22). Signal was observed with both probes, indicating that the centromere was composed of alpha-satellite DNA from both constituent chromosomes. Genotyping of the fetus and her parents with chromosome 18p STS marker D18S391 showed only the paternal 187 bp allele was present in the fetus, indicating that it was the maternal chromosome 18 involved in the der(18;22). This case and previous reports show that de novo unbalanced whole arm translocations are more likely to retain alpha-satellite sequences from the two chromosomes involved.     

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

We report a patient with Prader-Willi syndrome (PWS) and mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter. A maternal uniparental heterodisomy for chromosome 15 was present in all cells, defining the molecular basis for the PWS in this patient. The translocated distal 15q fragment was of paternal origin and was present as a jumping translocation, involving three different translocation partners, chromosomes 14q, 4q, and 16p. The recipient chromosomes appeared cytogenetically intact and interstitial telomere DNA sequences were present at the breakpoint junctions. This strongly suggests that the initial event leading to the translocation of distal 15q was a non-reciprocal translocation, with fusion between the 15q24 break-point and the telomeres of the recipient chromosomes. These observations are best explained by a partial zygotic trisomy rescue and comprise a previously undescribed mechanism leading to partial trisomy.     

Identification of the origin of centromeres in whole-arm translocations using fluorescent in situ hybridization with alpha-satellite DNA probes

We detected 2 patients with whole-arm translocations resulting in a derivative chromosome consisting of 18q and 21q. Because the breakpoints were near the centromere, classical cytogenetic techniques could not determine the centromeric origin of the derivative chromosomes. Using nonradioactive in situ hybridization with a chromosome 18 alpha-satellite DNA probe (D18Z1), the centromeres in the abnormal chromosomes were determined to be from chromosome 18. The abnormality in one patient resulted in monosomy 18p with a karyotype 45,XX, -18, -21, + der(18)t(18;21) (p11;q11)mat complement. The second patient with a 46,XX, -21, + der(18)t(18;21)(p11;q11) de novo karyotype had complete trisomy of 18q. In both cases the appropriate phenotype was observed.     

Balanced and unbalanced translocations in a multicentric series of 2843 patients with chronic lymphocytic leukemia

Chromosomal translocations in chronic lymphocytic leukemia (CLL) are very rare, and therefore systematic analysis of large series of cases is needed to allow the identification of recurrent rearrangements, breakpoints involved, and target genes. The aims of the present study were to identify new translocations and their clinical impact and to establish their frequency in a large cohort of 2843 CLL patients. By conventional cytogenetics 250 translocations were identified in 215 (7.5%) patients, 186 (74%) were apparently balanced and 64 (26%) were unbalanced. All chromosomes were involved in translocations, except Y chromosome. The chromosomes more frequently translocated were in decreasing frequency chromosomes 14, 18, 13, 17, 1, 6, 2, 3, 8, and 11. Translocations were found in the karyotypes either as the unique chromosomal abnormality (27%), associated with another alteration (24%), or as a part of a complex karyotype (CK, 48%). A large proportion of rearranged breakpoints involved genes related to CLL such as IGH (14q32), RB1, MIR15A, MIR16-1 (13q14), BCL2 (18q21), IGL (22q11.2), TP53 (17p13), IRF4 (6p25-p23), ATM (11q22), and CDK6 (7q21). Overall, 76 novel CLL translocations were identified, including a recurrent t(8;11)(p21;q21-23). Whole-genome sequencing and/or copy-number microarray data of 24 cases with translocations confirmed all rearrangements, enabled refinement of 3 karyotypes and all breakpoints at gene level. The projected survival and time to first treatment significantly decreased linearly with the number of translocations. In summary, this study allowed to establish the frequency of translocations (7.5%) and to identify new translocations in a cohort of 2843 CLL patients.     

Identification of cryptic imbalance in phenotypically normal and abnormal translocation carriers

Approximately one in 500 individuals carries a reciprocal translocation. Of the 121 monosomy 1p36 subjects ascertained by our laboratory, three independent cases involved unbalanced translocations of 1p and 9q, all of which were designated t(1;9)(p36.3;q34). These derivative chromosomes were inherited from balanced translocation carrier parents. To understand better the causes and consequences of chromosome breakage and rearrangement in the human genome, we characterized each derivative chromosome at the DNA sequence level and identified the junctions between 1p36 and 9q34. The breakpoint regions were unique in all individuals. Insertions and duplications were identified in two balanced translocation carrier parents and their unbalanced offspring. Sequence analyses revealed that the translocation breakpoints disrupted genes. This study demonstrates that apparently balanced reciprocal translocations in phenotypically normal carriers may have cryptic imbalance at the breakpoints. Because disrupted genes were identified in the phenotypically normal translocation carriers, caution should be exercised when interpreting data on phenotypically abnormal carriers with apparently balanced rearrangements that disrupt putative candidate genes.     

Parental origin determination in thirty de novo Robertsonian translocations

Cytogenetic heteromorphisms and restriction fragment length polymorphisms were used to assign the parental origins of 30 de novo non-homologous Robertsonian translocations. The balanced and unbalanced translocations studied included 20 rob(14q21q) four rob(13q14q) four rob(15q21q) one rob(13q15q), and one rob(13q21q). Significantly more maternally (26/30) than paternally (4/30) derived de novo translocations were noted and all rob(14q21q) ascertained through unbalanced probands (20/20) were maternal in origin. Interestingly, 12/13 probands who were trisomic and informative for proximal chromosome 21q loci were homozygous for the markers tested. Segregation (2:1) of the Robertsonian translocation into one daughter cell in meiosis I and subsequent failure of the chromosome 21 chromatids to separate in meiosis II may account for our observation of homozygosity for proximal chromosome 21 loci in the majority of de novo rearrangements tested. © 1992 Wiley-Liss, Inc.     

Identification of the origin of centromeres in whole-arm translocations using fluorescent in situ hybridization with α-satellite DNA probes

We detected 2 patients with whole-arm translocations resulting in a derivative chromosome consisting of 18q and 21q. Because the breakpoints were near the centromere, classical cytogenetic techniques could not determine the centromeric origin of the derivative chromosomes. Using nonradioactive in situ hybridization with a chromosome 18 α-satellite DNA probe (D18Z1), the centromeres in the abnormal chromosomes were determined to be from chromosome 18. The abnormality in one patient resulted in monosomy 18p with a karyotype 45, XX, ?18, ?21, + der(18)t(18;21) (p11;q11)mat complement. The second patient with a 46, XX, ?21, + der(18)t(18;21)(p11;q11) de novo karyotype had complete trisomy of 18q. In both cases the appropriate phenotype was observed.     

Minimal phenotype in a girl with trisomy 15q due to t(X;15)(q22.3;q11.2) translocation

Few cases of de novo unbalanced X;autosome translocations associated with a normal or mild dysmorphic phenotype have been described. We report a 3-year-old dizygotic female twin with prenatally ascertained increased nuchal translucency. Prenatal chromosome studies revealed nearly complete trisomy 15 due to a de novo unbalanced translocation t(X;15)(q22;q11.2) confirmed postnatally. A mild phenotype was observed with normal birth measurements, minor facial dysmorphic features (hypertelorism, short broad nose, and a relatively long philtrum), and moderate developmental delay at the age of 3 years in comparison to her male fraternal twin. Replication timing utilizing BrdU and acridine-orange staining showed that the der(X) chromosome was late-replicating with variable spreading of inactivation into the translocated 15q segment. The der(X) was determined to be of paternal origin by analyses of polymorphic markers and CGG-repeat at FMR1. Methylation analysis at the SNRPN locus and analysis of microsatellites on 15q revealed paternal isodisomy with double dosage for all markers and the unmethylated SNRPN gene. The Xq breakpoint was mapped within two overlapping BAC clones RP11-575K24 and RP13-483F6 at Xq22.3 and the 15q breakpoint to 15q11.2, within overlapping clones RP11-509A17 and RP11-382A4 that are all significantly enriched for LINE-1 elements (36.6%, 43.0%, 26.6%, 22.0%, respectively). We speculate that the attenuated phenotype may be due to inactivation spreading into 15q, potentially facilitated by the enrichment of LINE-1 elements at the breakpoints. In silico analysis of breakpoint regions revealed the presence of highly identical low-copy repeats (LCRs) at both breakpoints, potentially involved in generating the translocation.     

Partial monosomy of 7q32 in a case of de novo rcp(7;15)(q32;q15).

A de novo apparently balanced translocation between chromosomes 7 and 15 with breakpoints in q32 and q15 respectively is reported in a female child. Clinical features included general growth and psychomotor retardation, feeding problems, microcephaly, low set ears, a short neck, and brachydactyly. These findings suggested possible physical or functional partial monosomy of the 7q32 or 15q15 segments. The phenotype of this case is similar to other cases of 7q deletion.     

Parental origin determination in thirty de novo Robertsonian translocations.

Cytogenetic heteromorphisms and restriction fragment length polymorphisms were used to assign the parental origins of 30 de novo non-homologous Robertsonian translocations. The balanced and unbalanced translocations studied included 20 rob(14q21q) four rob(13q14q)four rob(15q21q) one rob(13q15q), and one rob(13q21q). Significantly more maternally (26/30) than paternally (4/30) derived de novo translocations were noted and all rob(14q21q) ascertained through unbalanced probands (20/20) were maternal in origin. Interestingly, 12/13 probands who were trisomic and informative for proximal chromosome 21q loci were homozygous for the markers tested. Segregation (2:1) of the Robertsonian translocation into one daughter cell in meiosis I and subsequent failure of the chromosome 21 chromatids to separate in meiosis II may account for our observation of homozygosity for proximal chromosome 21 loci in the majority of de novo rearrangements tested.     

Trisomy 1q generating translocations in Wilms tumor

Unbalanced translocations generating trisomy of 1q are common in Wilms tumor (WT). We present eight unbalanced 1q translocations from seven tumors and a review of the literature. An unbalanced translocation that results in a der(16)t(1q;16q) chromosome represents more than half of the published +1q generating translocations in WT. This translocation is also common to many other tumor types. Four of the tumors presented here contained this chromosome and,in two cases, it was the primary acquired cytogenetic abnormality within the tumor. The other four translocations involved 9q31, 9q34, 17p1?, and 21p11 as the partner to 1q. The chromosome 17 and 21 translocations occurred within the same tumor as apparently independent events. In contrast with the 16q translocations, these other translocations were secondary cytogenetic events, thereby indicating a role in tumor progression rather than initiation. Probes mapping to 1q12 and 1q21 were employed for fluorescence in situ hybridization and it was demonstrated that different 1q breakpoints are possible. In this series, the majority of breakpoints either mapped to 1q12 or were centromeric to this region.     

Jumping translocations of 11q in acute myeloid leukemia and 1q in follicular lymphoma

Jumping translocation is a rare cytogenetic aberration in leukemia and lymphoma, and its etiologic mechanisms are not clearly known. We report two cases with jumping translocations. One had follicular lymphoma and jumping translocations of 1q onto the telomeric regions of 5p, 9p, and 15q in three cell lines, co-existing with the specific translocation t(14;18)(q32;q21). The second case had acute myeloid leukemia (AML) and jumping translocations of 11q as the sole aberration, onto multiple derivative chromosomes in each of the abnormal cells. A total of 17 telomeric regions were seen as the recipients of 11q in this case, and 9q was always involved as one of the recipients in all abnormal cells. Fluorescence in situ hybridization (FISH) confirmed the identification of 11q material in the derivative chromosomes. While 1q has been the most common donor of acquired jumping translocations, this is the first report on jumping translocations of 11q. Different from all previously reported jumping translocations which involve only one recipient in each cell line and lead to a mosaic trisomy, multiple recipients in most of the abnormal cells in this case had led to a tetrasomy, or a pentasomy of 11q. The pattern of chromosome involvement as the recipients of 11q appears to show a continuing evolutionary process of jumping, stabilization, and spreading of the donor material into other chromosomes. Somatic recombinations between the interstitial telomeric or subtelomeric sequences of a derivative chromosome and the telomeric sequences of normal chromosomes are believed to be the underlying mechanism of jumping translocations and their clonal evolution.