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.     

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-reciporcal 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.     

Analysis of a familial three way translocation involving chromosomes 3q, 6q, and 15q by high resolution banding and fluorescent in situ hybridisation (FISH) shows two different unbalanced karyotypes in sibs.

We report on a familial three way translocation involving chromosomes 3, 6, and 15 identified by prometaphase banding and fluorescence in situ hybridisation (FISH). Two mentally retarded sibs with different phenotypic abnormalities, their phenotypically normal sister and mother, and two fetuses of the phenotypically normal sister were analysed. The terminal regions of chromosomes 3q, 6q, and 15q were involved in a reciprocal translocation, in addition to a paracentric inversion of the derivative chromosome 15. Conventional cytogenetic studies with high resolution GTG banding did not resolve this rearrangement. FISH using whole chromosome paints (WCPs) identified the chromosomal regions involved, except the aberrant region of 3q, which was undetectable with these probes. Investigation of this region with the subtelomeric FISH probe D3S1445/D3S1446 showed a balanced karyotype, 46,XX,t(3;15;6) (q29;q26.1;q26), inv der(15) (q15.1q26.1) in two adult females and one fetus. It was unbalanced in two sibs, showing two different types of unbalanced translocation resulting in partial trisomy 3q in combination with partial monosomy 6q in one patient and partial trisomy 15q with partial monosomy 6q in the other patient and one fetus. These represent apparently new chromosomal phenotypes.     

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.     

Additional complexity on human chromosome 15q: identification of a set of newly recognized duplicons (LCR15) on 15q11-q13, 15q24, and 15q26

Several cytogenetic alterations affect the distal part of the long arm of human chromosome 15, including recurrent rearrangements between 12p13 and 15q25, which cause congenital fibrosarcoma (CFS). We present here the construction of a BAC/PAC contig map that spans 2 Mb from the neurotrophin-3 receptor (NTRK3) gene region on 15q25.3 to the proximal end of the Bloom's syndrome region on 15q26.1, and the identification of a set of new chromosome 15 duplicons. The contig reveals the existence of several regions of sequence similarity with other chromosomes (6q, 7p, and 12p) and with other 15q cytogenetic bands (15q11-q13 and 15q24). One region of similarity maps on 15q11-q13, close to the Prader-Willi/Angelman syndromes (PWS/AS) imprinting center. The 12p similar sequence maps on 12p13, at a distance to the ets variant 6 (ETV6) gene that is equivalent on 15q26.1 to the distance to the NTRK3 gene. These two genes are the targets of the CFS recurrent translocations, suggesting that misalignments between these two chromosomes regions could facilitate recombination. The most striking similarity identified is based on a low copy repeat sequence, mainly present on human chromosome 15 (LCR15), which could be considered a newly recognized duplicon. At least 10 copies of this duplicon are present on chromosome 15, mainly on 15q24 and 15q26. One copy is located close to a HERC2 sequence on the distal end of the PWS/AS region, three around the lysyl oxidase-like (LOXL1) gene on 15q24, and three on 15q26, one of which close to the IQ motif containing GTPase-activating protein 1 (IQGAP1) gene on 15q26.1. These LCR15 span between 13 and 22 kb and contain high identities with the golgin-like protein (GLP) and the SH3 domain-containing protein (SH3P18) gene sequences and have the characteristics of duplicons. Because duplicons flank chromosome regions that are rearranged in human genomic disorders, the LCR15 described here could represent new elements of rearrangements affecting different regions of human chromosome 15q.     

Jumping translocation with partial duplications and triplications of chromosomes 7 and 15

We report a 2-year-old female with seizures, mild dysmorphic features and a jumping translocation involving chromosome 15 that results in multiple cell lines with partial duplications and triplications of chromosomes 7 and 15. Fluorescent in situ hybridization (FISH) and chromosome microdissection were used to identify the complex nature of the jumping translocation. Interstitial telomeres were observed at the jumping translocation sites. The jumping chromosome rearrangement was also found to have a partial duplication of 7p as demonstrated by chromosome microdissection. Despite these paritial duplications and triplications of chromosomes 7 and 15, the child does not have major birth defects. She does have mild sensorimotor delays. A review of non-Robertsonian jumping translocations is provided.     

Two cases of partial trisomy 21 (pter-q22.1) without the major features of Down syndrome

We report two cases of partial trisomy 21 with clinical features distinct from Down syndrome (DS). These patients presented with moderate mental retardation and short stature, but the typical facial appearance of DS was not observed. Each patient had a similarly sized extra chromosome 21. We performed FISH analysis to examine whether deletions of reported approximately 5 Mb DS critical region (DSCR) might be associated with unusual clinical features in these cases. The results showed that each of their extra chromosomes 21 contained a distal part of chromosome 3p or 14q at the telomeric region of chromosome 21q. The translocation breakpoint of 21q for each patient was located on the centromeric side of DSCR (DSCR was deleted) and the sizes of partial trisomy 21 in respective patients are approximately 34.5 (21pter-q22.12) and approximately 33.0 Mb (21pter-q22.11). In one patient, the additional region of the short arm of chromosome 3 was 3pter-p26.1 from maternal origin, measuring approximately 9 Mb in size. The second patient had an extra 14q32.1-qter of maternal origin, measuring approximately 14 Mb in size. These are one of the shortest partial distal trisomy among reported cases. Taken together, two patients with partial trisomy 21 lack all of DSCR on 21q22, and their distinct clinical features are likely caused by the genes located at 21pter-q22.1 and the distal part of chromosome 3p or 14q.     

Deletions of proximal 15q and non-classical Prader-Willi syndrome phenotypes

A deletion of the long arm of chromosome 15 (usually involving bands 15q11-q12) has been seen in approximately 50% of Prader-Willi syndrome (PWS) patients [Ledbetter et al, 1982]. However, 14 patients with non-PWS (or atypical PWS) phenotype with 15q deletion indicate great clinical variability. A deletion was found in a propositus with a de novo translocation [45,XY, -15, -22, +rec(15;22) (22pter----22q13.2::15q14----15qter)], who had anomalies not normally observed in PWS patients. Activities of several enzymes mapped to the involved chromosomes were studied in the patient and control individuals. A 50% decrease in the level of arylsulfatase-A confirmed a small deletion in 22q(22q13.2----qter), and additional studies localized more precisely the loci for alpha-mannosidase (cytoplasmic) and beta-galactosidase.     

Inherited partial trisomy #15 complicated by neuroblastoma

The proband in this study had multiple congenital malformations and a constitutional 46,XY,-13, + der(13),t(13;15)(q34;q23)mat chromosome complement. A bone marrow aspirate revealed neuroblastoma, and cytogenetic studies on tumor cells revealed, in addition to the partial trisomy #15 and probable partial monosomy #13, hypotetraploidy with a mean chromosome number of 82-84, including 3 or 4 copies of each autosome, 2 X chromosomes, no Y chromosome, and a marker. Translocations involving chromosomes #1, #2, #3, #7, and #14 were present, along with multiple double minutes. The possibility that the inherited partial trisomy #15 (and/or partial chromosome #13 monosomy) predisposed to neuroblastoma and additional chromosome changes in this tumor is discussed.     

Prader-Willi syndrome in a child with mosaic trisomy 15 and mosaic triplo-X: a molecular analysis.

A 3.3 year old girl with Prader-Willi syndrome (PWS) and mosaicism for two aneuploidies, 47,XXX and 47,XX,+15, is presented. The triplo-X cell line was found in white blood cells and fibroblasts, the trisomy 15 cell line in 50% of the fibroblasts. Using methylation studies of the PWS critical region and by polymorphic microsatellite analysis, the existence of uniparental maternal heterodisomy for chromosome 15 was shown in white blood cells. This provided a molecular explanation for the PWS in this child. In fibrolasts, an additional paternal allele was detected for markers on chromosome 15, which is in agreement with the presence of mosaicism for trisomy 15 in these cells. This example provides direct evidence for trisomic rescue by reduction to disomy as a possible basis for PWS. Whereas the trisomy 15 was caused by a maternal meiosis I error, the triplo-X resulted from a postzygotic gain of a maternal X chromosome, as shown by the finding of two identical maternal X chromosomes in the 47,XXX cell line. Because the triplo-X and the trisomy 15 were present in different cell lines, gain of an X chromosome occurred either in the same cell division as the trisomy 15 rescue or shortly before or after.     

Familial translocation t(Y;15)(q12;p11) and de novo deletion of the Prader-Willi syndrome (PWS) critical region on 15q11-q13

We describe a 17-year-old girl with mild Prader-Willi syndrome (PWS) due to 15q11-q13 deletion. The deletion occurred on a paternal chromosome 15 already involved in a translocation, t(Y;15)(q12;p11), the latter being present in five other, phenotypically normal individuals in three generations. This appears to be the first case of PWS in which the causative 15q11-q13 deletion occurred on a chromosome involved in a familial translocation, but with breakpoints considerably distal to those of the familial rearrangement. The translocation could predispose to additional rearrangements occurring during meiosis and/or mitosis or, alternatively, the association of two cytogenetic anomalies on the same chromosome could be fortuitous. Am. J. Med. Genet. 70: 222–228, 1997. © 1997 Wiley-Liss, Inc.     

Cytogenetic study in multiple myeloma

Ten patients with multiple myeloma (MM) were studied cytogenetically, using the G-banding technique. It was found that five patients had a normal karyotype, whereas five patients exhibited various chromosomal abnormalities. The presence of marker chromosomes was a consistent finding. Among those, the 14q+ marker chromosome was present in three cases, partial or complete trisomy for 1q was detected in four cases, and chromosome #6 was involved in two cases. In one case the 14q+ marker chromosome was determined to result from a translocation between chromosomes #11 and #14. In one patient with Bence Jones κ multiple myeloma, there was a translocation between chromosomes #2 and #8.     

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2)

Maternal uniparental disomy (UPD) for chromosome 15 is responsible for an estimated 30% of cases of Prader-Willi syndrome (PWS). We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient (J.B.), a 17-year-old white male with PWS, was found to have 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15, and distal chromosome arm 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J.B. Methylation analysis at exon alpha of the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) gene showed a pattern characteristic of only the maternal chromosome 15 in J.B. Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma-aminobutyric acid receptor beta3 subunit (GABRB3) locus. A niece (B.B.) with 45 chromosomes and the derivative 3 but without the der(15) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p. Uniparental disomy associated with unbalanced segregation of non-Robertsonian translocations has been reported previously but has not, to our knowledge, been observed in a case of PWS. Furthermore, our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS. Am. J. Med. Genet. 78:134–139, 1998. © 1998 Wiley-Liss, Inc.     

Familial robertsonian translocation 15;21 and rare paracentric inv(21): unexpected re-inversion in a child with translocation trisomy 21

We present a family with a Robertsonian translocation (RT) 15;21 and an inv(21)(q21.1q22.1) which was ascertained after the birth of a child with Down syndrome. Karyotyping revealed a translocation trisomy 21 in the patient. The mother was a carrier of a paternally inherited RT 15;21. Additionally, she and her mother showed a rare paracentric inversion of chromosome 21 which could not be observed in the Down syndrome patient. Thus, we concluded that the two free chromosomes 21 in the patient were of paternal origin. Remarkably, short tandem repeat (STR) typing revealed that the proband showed one paternal allele but two maternal alleles, indicating a maternal origin of the supernumerary chromosome 21. Due to the fact that chromosome analysis showed structurally normal chromosomes 21, a re-inversion of the free maternally inherited chromosome 21 must have occurred. Re-inversion and meiotic segregation error may have been co-incidental but unrelated events. Alternatively, the inversion or RT could have predisposed to maternal non-disjunction.     

Trisomy 15q25.2-qter in an autistic child: genotype-phenotype correlations

We report on the case of a male child with autistic disorder, postnatal overgrowth, and a minor brain malformation. Karyotyping and fluorescent in situ hybridization (FISH) analysis showed the presence of an extra copy of the distal portion of chromosome 15q (15q25.2-qter) transposed to chromosome 15p leading to 15q25.2-qter pure trisomy. This karyotype-phenotype study further supports the evidence for a specific phenotype related to trisomy 15q25 or 26-qter and suggests that distal chromosome 15q may be implicated in specific behavioral phenotypes.     

Down syndrome: characterisation of a case with partial trisomy of chromosome 21 owing to a paternal balanced translocation (15;21) (q26;q22.1) by FISH.

A patient with a typical Down syndrome (DS) phenotype and a normal karyotype was studied by FISH. Using painting probes, we found that the patient had partial trisomy of chromosome 21 owing to an unbalanced translocation t(15;21) (q26; q22.1) of paternal origin. To correlate genotype with phenotype as accurately as possible, we localised the breakpoint using a contig of YACs from the long arm of chromosome 21 as probes and performed FISH. We ended up with two YACs, the most telomeric giving signal on the der (15) in addition to signal on the normal chromosome 21 and the most centromeric giving signal only on both normal chromosomes 21. From these results we could conclude that the breakpoint must be located within the region encompassing YACs 280B1 and 814C1, most likely near one end of either YAC or between them, since neither YAC814C1 nor 280B1 crossed the breakpoint (most likely between marker D21S304 and marker D21S302) onband 21q22.1. The same study was performed on the chromosomes of the father and of a sister and a brother of the patient; all three carried a balanced translocation between chromosomes 15 and 21 and had a normal phenotype. We also performed a prenatal study using FISH for the sister. The fetus was also a carrier of the balanced translocation.     

t(15;21)(q15;q22.1)pat resulting in partial trisomy and partial monosomy of chromosomes 15 and 21 in two offspring

Two sibs, carriers of unbalanced products of the translocation t(15;21)(q15;q22.1)pat, are described. The sister had Prader-Willi syndrome due to deletion 15 (pter > q15) and partial trisomy 21 (pter > q22.1); her brother had partial trisomy 15 (pter > q15) and partial monosomy 21 (pter > q22.1). The translocation breakpoint on chromosome 21 was located proximal to the SOD1 gene, within a region of 4.0 cM (2.3 Mb) between the loci D21S217 and D21S213. The correlations between the clinical presentation and the molecular findings of the two sibs are discussed in relation to other patients with partial trisomy and monosomy 21. © 1996 Wiley-Liss, Inc.     

Identification of two de novo partial trisomies by comparative genomic hybridization

We report the use of comparative genomic hybridization (CGH) to define the extra chromosome region present in two de novo partial trisomies 15q25-qter and Xp21-pter, which could not be clarified by conventional G-banding. Investigation with fluorescence in situ hybridization (FISH) revealed that the partial trisomy corresponded to an unbalanced translocation between Y and 15 chromosomes in 1 patient and an unbalanced X/X reorganization in the other patient. The combination of classical karyotyping, CGH, and FISH is useful for the identification and characterization of partial trisomies in clinical diagnostic laboratories, in order to delineate the chromosome regions implicated in specific clinical disorders.     

Submicroscopic deletion 9(q34.3) and duplication 19(p13.3): identified by subtelomere specific FISH probes

Submicroscopic rearrangements involving chromosome ends are responsible for the unexplained mental retardation and multiple congenital anomalies observed in a number of patients. We have studied a patient with mental retardation, significant microcephaly, alopecia universalis, and other anomalies who carries an unbalanced segregant from a cryptic reciprocal translocation involving chromosomes 9 and 19. FISH studies using subtelomere specific probes revealed a derivative chromosome 9 in which the 9q subtelomeric sequence has been replaced by 19p subtelomeric sequence. As a result, the patient has partial monosomy 9q and partial trisomy 19p. The patient inherited the derivative 9 from his father, who carries a cryptic apparently balanced reciprocal translocation involving the terminal regions of 9q and 19p. This case is exceptional in that reports of rearrangements involving distal chromosome 9q and 19p are rare. This study demonstrates the utility of subtelomere specific FISH probes for detecting cryptic subtelomeric rearrangements in patients with idiopathic mental retardation and normal appearing karyotypes.     

Paternal uniparental disomy in a child with a balanced 15;15 translocation and Angelman syndrome

Chromosome 15 (15q11-q13) abnormalities cause two distinct conditions, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). We present the first case of a child with a balanced 15;15 translocation and AS in whom molecular studies were crucial in confirming a diagnosis. DNA polymorphisms demonstrated paternal uniparental disomy for chromosome 15, consistent with the diagnosis of AS. The molecular studies also showed the patient to be homozygous at all loci for which the father was heterozygous, suggesting that the structural rearrangement was an isochromosome 15q and not a Robertsonian translocation. © 1993 Wiley-Liss, Inc.