Fish mapping of a translocation breakpoint at 6q21 (or q22) in a patient with heterotaxia

Summary Heterotaxia is a congenital lateralization defect of visceral organs. As several single-genes that act on the formation of left-right asymmetry during embryogenesis have been identified in animals, a defect in the similar system may play a role in heterotaxia in man. We previously reported a Japanese girl with heterotaxia associated with ade novo balanced translocation (6;18)(q21 or q22;q21.3 or q22). In the present study, based on a hypothesis that one of the putative situs-determining genes is disrupted at a breakpoint of the translocation, we first isolated a yeast artificial chromosome (YAC) clone covering a breakpoint, 6q21 (or q22) of the translocation. Then, using STSs mapped on the YAC, we isolated bacterial artificial chromosome (BAC) clones spanning the breakpoint. FISH analysis using the BAC clones as probes revealed that the breakpoint is confined to a segment between two STS loci, WI-4066 and the CHLC.GATA6B06.192, within a genetic distance of 1.4 cM. The human connexin43 gene was not disrupted in our patient, although mutations of this gene have been reported in patients with complex heart disease and heterotaxia. The molecular localization of the translocation breakpoint in our patient may contribute to the positional cloning of a putative heterotaxia gene.     

Chromosome 18 breakpoint in t(11;18)(q21;q21) translocation associated with MALT lymphoma is proximal to BCL2 and distal to DCC

The t(11;18)(q21;q21) translocation has recently been identified as a recurring chromosomal abnormality in a subset of extranodal marginal zone B‐cell lymphoma, a low‐grade lymphoma of mucosa‐associated lymphoid tissue (MALT). Neither the 11q21 nor the 18q21 breakpoints have been characterized by molecular genetic analysis. As a prelude to isolation of the gene(s) involved in this translocation, we have mapped the 18q21 breakpoint region by fluorescence in situ hybridization (FISH) of YAC and PAC clones. We mapped 37 YACs assigned to a 29‐cM region within the chromosomal band 18q21. Using nine of these YACs in single‐ and/or dual‐color FISH to analyze three cases of MALT lymphomas with the t(11;18)(q21;q21) translocation, we localized the breakpoints within a 1.6‐Mb nonchimeric YAC (938E1). This YAC is useful for the detection of the translocation in metaphase and in interphase cells. A nonchimeric YAC contig of an 8‐cM region around the breakpoint comprising nine YACs and a PAC contig of YAC 938E1 were constructed, which enabled the refinement of the breakpoint region in the proximal region of the YAC within a <820‐kb segment. This breakpoint is proximal to the BCL2 locus and distal to DCC and DPC4 loci in chromosomal band 18q21. Genes Chromosomes Cancer 24:156–159, 1999. © 1999 Wiley‐Liss, Inc.     

A novel case of infantile sacral teratoma and a constitutional t(12;15)(q13;q25) pat

Cytogenetic analysis of peripheral lymphocytes of an infantile patient with a sacral teratoma revealed a constitutional translocation (12;15)(q13;q25) pat. The same translocation was found in four additional relatives. Loss of heterozygosity analysis of the patient's tumor material showed retention of both translocation-derived chromosomes. Since allelic loss in the 12q13 region has been observed in germ cell tumors, we hypothesize that disregulation of genes located at or near the 12q13 breakpoint may be related to the development of this sacral teratoma. As a first step towards the identification of these genes, a 12q13 genomic contig that spans the breakpoint has been constructed.     

Molecular mapping of the chromosome 11 breakpoint of t(11;17)(q13;q21) in a t(11;14)(q13;q32)-positive B non-Hodgkin's lymphoma

The FAU gene is the cellular homologue of the viral FOX sequences in the genome of the Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV); the viral FOX sequences have been shown to increase the transforming capacity of FBR-MuSV in vitro. The human FAU gene has recently been isolated, characterized, and mapped to chromosome band 11q13. Here, we report results of fluorescence in situ hybridization (FISH) analysis which indicate that the FAU gene maps proximally to the putative oncogene BCL1 at 11q13. Furthermore, we identified a t(11;17)(q13;q21) translocation in tumor cells of a t(11;14)(q13;q32)-positive B-cell non-Hodgkin's lymphoma patient by FISH analysis using a FAU containing cosmid clone as molecular probe and by double-colour chromosome painting analysis using chromosome 11- and chromosome 17-specific painting probes. The position of the chromosome 11 breakpoint of the t(11;17) translocation was pinpointed to a human DNA region around the FAU gene of about 40 kbp. © 1993 Wiley-Liss, Inc.     

t(11;18)(q21;q21.1): A recurring translocation in lymphomas of mucosa-associated lymphoid tissue (malt)?

A distinct subtype of extranodal malignant lymphoma derived from mucosa-associated lymphoid tissues (MALT) has recently been defined. We have detected an acquired t(11;18)(q21;q21.1) in a patient with a MALT lymphoma of the stomach. This translocation has previously been described in two other patients with extranodal lymphoma. The BCL2 oncogene, which is located at band 18q21.3 and is activated by the t(14;18)(q32;q21) in follicular lymphoma, was not rearranged in this case. This newly identified t(11;18) may be a recurring translocation specifically associated with MALT lymphomas. Genes located at the breakpoint sites of chromosome 11 and/or chromosome 18 may be crucial to the pathogenesis of this type of malignant lymphoma.     

Localization of the synovial sarcoma t(X;18)(p11.2;q11.2) breakpoint by fluorescence in situ hybridization.

A high proportion of synovial sarcomas contain a chromosome translocation t(X;18)(p11.2;q11.2). We have previously used somatic cell hybrids derived from an established cell line, SS255, to map the X chromosome breakpoint to the interval flanked by the markers DXS14 and DXS146. In this study we have examined these hybrids with thirteen additional markers located at Xp11.3-Xcen, by Southern hybridization. Based on these results we have delimited the breakpoint as follows Xpter-DXS228-(UBE1-OATL1-TIMP-DXS226 )-(DXS255-TFE3-ELK1-DXS146)-OATL2- X;18-(DXS14-DXS422-DXS423-DXS674-DXS679)-+ ++Xcen. Confirmation of the breakpoint location has been obtained by analysis of two synovial sarcoma cell lines, SS255 and HA2243, using fluorescence in situ hybridization. A 350kb YAC probe spanning the DXS423 locus hybridized only to the derivative X chromosome, showing that it maps proximal to the breakpoint. Two YAC probes of 300kb and 450kb, containing the OATL2 locus, hybridized to both derivative chromosomes, indicating that these YACs span the translocation breakpoint. Similar results were obtained with both cell lines. The identification of YACs that span the t(X;18) breakpoint now facilitates a strategy for cloning candidate genes from this precisely defined region.     

Identification of a yeast artificial chromosome (YAC) spanning the synovial sarcoma-specific t(X;18)(p11.2;q11.2) breakpoint

A somatic cell hybrid containing the synovial sarcoma-associated t(X;18)(p11.2;q11.2) derivative (der(X)) chromosome was used to characterize the translocation breakpoint region on the X chromosome. By using Southern hybridization of DNA from this der(X) hybrid in conjunction with Xp-region specific radiation reduced cell hybrids and probes, it was found that this breakpoint maps within the ornithine aminotransferase (OAT) L1 cluster. A yeast artificial chromosome (YAC) clone (OAT YAC2) which hybridizes to a human OAT cDNA probe and is known to contain part of the OATL1 cluster was selected and used to confirm these results both by fluorescence in situ hybridization on synovial sarcoma patient material and by hybridization of its end-clones to the der(X) containing hybrid cells. It was found that indeed the human Xp sequences contained within this YAC are split as a consequence of the (X;18) translocation. Therefore, we conclude that OAT YAC2 spans the synovial sarcoma-specific translocation breakpoint and, as such, may serve as an ideal starting point from which the gene(s) involved in the development of this soft tissue tumor can be isolated. © 1993 Wiley-Liss, Inc.     

A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: Molecular analysis of the chromosome 7 breakpoint

Autism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7–specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region. © 2001 Wiley‐Liss, Inc.     

Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein to 18q22.3

Two related patients with similar clinical features consisting of a few dysmorphic signs and psychiatric disturbance were reported to have a partial trisomy of chromosomes 15(pter-q13.3) and 18(q23-qter) deriving from a familial translocation t(15;18). One patient is affected by bipolar disorder and the other by schizoaffective disorder. Both cases have a predominantly affective course; nevertheless, a clear diagnosis is difficult in the first patient, who is 15 years of age, and only a longitudinal course will allow us to establish a definite diagnosis. The possibility that these two pathologies belong to a single category is discussed, and the presence of a susceptibility locus on chromosome 18 is hypothesized. Cytogenetic data, FISH, and DNA studies indicate that the myelin basic protein (MPB) gene is not involved in the translocation, and localize it centromeric to the breakpoint on chromosome 18(q22.3). Thus, it is unlikely to be involved in the disease. © 1996 Wiley-Liss, Inc.     

A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint.

Autism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7-specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region.     

Molecular characterization of the breakpoint region associated with a constitutional t(2;15)(q34;q26) in a patient with multiple myeloma

The molecular cloning of the translocation breakpoints from constitutional chromosome rearrangements in patients with a variety of human diseases has consistently led to the isolation of genes important in the development of the phenotype. We used fluorescence in situ hybridization (FISH) to analyze the breakpoint region of a constitutional chromosome translocation involving regions 2q34 and 15q26 observed in a patient with multiple myeloma (MM), a malignant disorder of plasma cells secreting monoclonal immunoglobulin. FISH analysis of this rearrangement showed that the chromosome 2-specific yeast artificial chromosome (YAC) 914E7 and the chromosome 15-specific YAC 757H6 span the translocation breakpoints, respectively. In order to characterize the location of the breakpoints further, somatic cell hybrids were constructed between mouse NIH3T3 cells and t(2;15)-bearing lymphoblastoid cells. Using these somatic cell hybrids, we have shown that the breakpoint on chromosome 2 lies between D2S3007 and D2S3004 and the chromosome 15 breakpoint lies between D15S107 and WI5967 (D15S836). YAC fragmentation has been used to define a 350 kb region containing the 15q26 breakpoint.     

Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22)

The constitutional t(11;22)(q23;q11) is the only known recurrent, non-Robertsonian translocation. To analyze the genomic structure of the breakpoint, we have cloned the junction fragments from the der(11) and der(22) of a t(11;22) balanced carrier. On chromosome 11 the translocation occurs within a short, palindromic AT-rich region (ATRR). Likewise, the breakpoint on chromosome 22 has been localized within an ATRR that is part of a larger palindrome. Interestingly, the 22q11 breakpoint falls within one of the 'unclonable' gaps in the genomic sequence. Further, a sequenced chromosome 11 BAC clone, spanning the t(11;22) breakpoint in 11q23, is deleted within the palindromic ATRR, suggesting instability of this region in bacterial clones. Several unrelated t(11;22) families demonstrate similar breakpoints on both chromosomes, indicating that their translocations are within the same palindrome. It is likely that the palindromic ATRRs produce unstable DNA structures in 22q11 and 11q23 that are responsible for the recurrent t(11;22) translocation.     

Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/chronic tic disorder at 18q22

Gilles de la Tourette syndrome (GTS), obsessive compulsive disorder (OCD), and chronic tic disorder (CTD) are chronic, potentially debilitating neuropsychiatric disorders that often cluster in families. Comorbidity data and family and linkage studies support the hypothesis that these phenotypes, in some cases, share a common etiology. Studies of chromosomal abnormalities associated with this phenotypic spectrum further show that GTS, OCD, and CTD may represent alternate manifestations of a shared genetic condition. We report on a 14-year-old girl with severe OCD and a t(2;18)(p12;q22) translocation. The patient's chromosome 18 breakpoint localizes to the same chromosomal band as two previously reported rearrangements associated with GTS, OCD, and CTD, and fine maps to a genomic position approximately 5 Mb from these rearrangements. The clustering of these three breakpoints within a relatively small genetic interval suggests that 18q22 is a promising region for containing a gene or genes of etiologic importance in the development of the GTS/OCD/CTD phenotypic spectrum.     

t(14;19)(q32;q13): a recurrent translocation in B-cell precursor acute lymphoblastic leukemia

The recurrent t(14;19)(q32;q13) translocation associated with chronic B-cell lymphoproliferative disorders, such as atypical chronic lymphocytic leukemia, results in the juxtaposition of the IGH@ and BCL3 genes and subsequent overexpression of BCL3. We report six patients with B-cell precursor acute lymphoblastic leukemia who have a cytogenetically identical translocation with different breakpoints at the molecular level. Fluorescence in situ hybridization with locus-specific probes confirmed the involvement of the IGH@ gene but showed that the breakpoint on 19q13 lay outside the region documented in t(14;19)(q32;q13)-positive chronic lymphocytic leukemia. This newly described translocation constitutes a distinct cytogenetic subgroup that is confined to older children and younger adults with B-cell precursor acute lymphoblastic leukemia.     

Tricho-rhino-phalangeal syndrome type I (TRP I) due to an apparently balanced translocation involving 8q24

Tricho-rhino-phalangeal (TRP) syndromes type I and II are caused by a defective gene located on chromosome 8q24.1. We report a family with 2 sibs affected with TRP type I in combination with an apparently balanced chromosome (8;18) translocation involving 8q24.11. It is very likely that the 8q24 translocation breakpoint is physically linked to the TRP gene(s), thereby facilitating future efforts to clone the TRP gene(s). © 1993 Wiley-Liss, Inc.     

Candidate region for Gilles de la Tourette syndrome at 7q31

Gilles de la Tourette Syndrome (GTS) is a complex neuropsychiatric disorder characterized by motor and vocal tics. The cause of this syndrome is unknown, although based on family studies there is evidence of a strong genetic component. We report on a 13‐year‐old boy with GTS, minor physical anomalies, and a de novo partial duplication of chromosome 7q [dup(7)(q22.1–q31.1)]. The distal breakpoint in our patient is similar to the breakpoint of an apparently balanced familial translocation t(7;18) segregating with GTS. Together, these cases provide evidence that a gene located in the breakpoint region at 7q31 can be involved in the formation of GTS. © 2001 Wiley‐Liss, Inc.     

Candidate region for Gilles de la Tourette syndrome at 7q31.

Gilles de la Tourette Syndrome (GTS) is a complex neuropsychiatric disorder characterized by motor and vocal tics. The cause of this syndrome is unknown, although based on family studies there is evidence of a strong genetic component. We report on a 13-year-old boy with GTS, minor physical anomalies, and a de novo partial duplication of chromosome 7q [dup(7)(q22.1-q31.1)]. The distal breakpoint in our patient is similar to the breakpoint of an apparently balanced familial translocation t(7;18) segregating with GTS. Together, these cases provide evidence that a gene located in the breakpoint region at 7q31 can be involved in the formation of GTS.     

Translocation t(12;22)(q13;q12.2–12.3) in a clear cell sarcoma of tendons and aponeuroses

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), + der(7)t(7;18)(p11.2;q21.3), + 8, + der(8;17)(q10;q10),t(12;22)(q13;q12.2–12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma. © 1993 Wiley-Liss, Inc.