Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3.

Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.     

A yeast artificial chromosome telomere clone spanning a possible location of the Huntington disease gene

The Huntington disease (HD) gene has been mapped to the most distal subband of chromosome 4p. Analysis of recombination events has not provided an unequivocal location of the HD gene, but it indicates a position very close to the telomere as one possibility. We have constructed a yeast artificial chromosome (YAC) vector (containing a rare-cutter polylinker) for the cloning of mammalian telomeres, used it to prepare a BssHII-telomere library with DNA from an individual homozygous for HD, and have identified a 115-kb clone containing the telomere of 4p. One probable recombinant would confine the telomeric candidate location for the gene to the region covered by the YAC, which makes it possible that the clone described here contains the HD locus in its mutant form.     

Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins

We report here the identification and characterization of a novel gene (AUTS2) that spans the 7q11.2 breakpoint in a monozygotic twin pair concordant for autism and a t(7;20) (q11.2; p11.2) translocation. AUTS2 is 1.2 Mb and has 19 exons. The predicted protein is 1295 amino acids and does not correspond to any known protein. DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus no autism-specific mutation was observed. Association analysis with two exonic polymorphic sites and linkage analysis of four dinucleotide repeat markers, two within and two flanking AUTS2, was negative. Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here.     

Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual

The results of genetic linkage studies for autism have suggested that a susceptibility locus for the disease is located on the long arm of chromosome 7 (7q). An autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q implicated by genetic studies was identified. A novel gene known as "RAY1" (or "FAM4A1") was found to be directly interrupted by the translocation breakpoint. The gene, which was found to be encoded by 16 exons with evidence of alternative splicing, spanned > or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding region mutations are unlikely to be involved in the etiology of autism. Apparent homologues of RAY1 have also been identified in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes share similar splicing patterns, and their predicted protein products are 98% identical.     

Molecular mapping of a translocation breakpoint at 14q13 in a patient with mirror-image polydactyly of hands and feet

Mirror hands and feet (MIM, 135750) is a rare congenital anomaly, and mirror-image polydactyly is considered to be a variant of mirror hands and feet. To our knowledge, seven patients with the disorder have been reported in the literature. Parent-to-child transmission was reported in two families, which may indicate a single-gene defect inherited in an autosomal dominant fashion. We had previously encountered a boy with mirror-image polydactyly whose karyotype showed 46,XY,t(2;14) (p23.3;q13) de novo. We hypothesized that at least one of the putative genes responsible for the determination of an anterior-posterior limb pattern is disrupted by a translocation breakpoint. In this study, we identified a yeast artificial chromosome clone spanning a translocation breakpoint at 14q13, and the breakpoint was confirmed to be located between two loci, AFM200ZH4 and D14S306, within a genetic distance of 0.6 cM. Received: 25 September 1996 / Revised: 6 December 1996     

A chromosome 19 clone from a translocation breakpoint shows close linkage and linkage disequilibrium with myotonic dystrophy

The gene for myotonic dystrophy (DM), the most common form of adult muscular dystrophy, is situated on the proximal long arm of chromosome 19. Although there exist markers that are tightly linked to the DM locus, its precise location is unknown. The identification and characterization of additional DNA probes closely linked to the DM locus continue to be priorities. In this study, we report on the linkage between a new DNA marker, designated p alpha 1.4P, and the DM locus in 50 families. The probe p alpha 1.4P was derived from a cloned breakpoint junction fragment from the chromosomal translocation t(14;19)(q32;q13.1). This translocation has been previously described in some cases of chronic lymphocytic leukemia. We have identified a BanI restriction fragment length polymorphism that is detected by p alpha 1.4P. Segregation analysis between this RFLP and DM revealed close linkage between the two loci (lod = 10.95, theta = 0). Furthermore, statistical evidence for linkage disequilibrium between p alpha 1.4P and the DM locus in a French Canadian population was found. Finally, by means of a somatic cell hybrid mapping panel, p alpha 1.4P was sublocalized to 19q12----19q13.2.     

The donor chromosome breakpoint for a jumping translocation is associated with large low-copy repeats in 21q21.3

Jumping translocations (JTs) are very rare chromosome aberrations, usually identified in tumors. We report a constitutional JT between donor chromosome 21q21.3-->qter and recipients 13qter and 18qter, resulting in an approximately 15.5-Mb proximal deletion 21q in a girl with mild developmental delay and minor dysmorphic features. Using fluorescence in situ hybridization (FISH) studies, we identified an approximately 550-kb complex inter- and intra-chromosomal low-copy repeat (LCR) adjacent to the 21q21.3 translocation breakpoint. On the recipient chromosomes 13qter and 18qter, the telomeric sequences TTAGGG were retained. Genotyping revealed that the deletion was of maternal origin. We propose that genome architecture involving LCRs may be a major mechanism responsible for the origin of jumping translocations.     

Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome (SLOS; also known as "RSH syndrome" [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Delta7-reductase (7-DHC reductase; E.C.1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Delta7-reductase. We cloned cDNA encoding a human sterol Delta7-reductase (DHCR7) on the basis of its homology with the sterol Delta7-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Delta7-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.     

Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint.

A Hispanic girl with Lowe oculocerebrorenal syndrome (OCRL), an X-linked recessive condition characterized by cataracts, glaucoma, mental retardation, and proteinuria, is reported. A balanced X;20 chromosomal translocation with the X chromosome breakpoint at q26.1 was found with high-resolution trypsin-Giemsa banding. Somatic cell hybridization was used to separate the X chromosome derivative and the chromosome 20 derivative in order to position, with respect to the translocation breakpoint, several DNA loci that are linked to the Lowe syndrome locus (Xq24-q26). DXS10 and DXS53 were found to be distal to the breakpoint, whereas DXS37 and DXS42 were located proximal to it. These studies suggest that the OCRL locus lies in the region between these probes. The translocation chromosome originated from an unaffected male without a visible translocation, indicating that the most likely cause of OCRL in this patient is the de novo translocation that disrupted the OCRL locus.     

In situ hybridization and translocation breakpoint mapping. III. DiGeorge syndrome with partial monosomy of chromosome 22

We have performed in situ hybridization of a probe for the lambda IGLC constant region to metaphase spreads from two DiGeorge syndrome (DGS)-related chromosomal rearrangements with breakpoints in 22q11. In this study we have demonstrated that the breakpoints are proximal to the lambda IGLC constant region cluster. Thus, at the molecular level, DGS-related breakpoints can be distinguished from the 22q11 breakpoint of CML, but not from the 8;22 translocation of Burkitt lymphoma or from the 21;22 translocations that we have previously studied.     

Molecular analysis of a t(7;14)(q35;q32) chromosome translocation in a T cell leukemia of a patient with ataxia telangiectasia

Molecular analysis of somatic cell hybrids derived from T cells carrying a t(7;14)(q35;q32) chromosomal translocation from a patient with ataxia telangiectasia and T cell leukemia indicates that the breakpoint on chromosome 14 is proximal to the IgH locus and to the D14S1 locus, while the breakpoint on chromosome 7 involves the T cell receptor beta chain locus immediately 5' to J beta 1.5 on chromosome 7. The separation of V beta and C beta observed in somatic cell hybrids defined the orientation of the T cell receptor beta chain locus on chromosome 7 where the V beta genes are centromeric and the C beta genes are telomeric. A novel chromosomal alteration, undetected cytogenetically, was revealed as being an inversion with duplication of the distal band of chromosome 14q32. The importance of the 14q32 region in the leukemogenic process is discussed.     

Inv(14) with distal breakpoint in 14q32.1 in three cases of T cell lymphoma

Summary The distal breakpoint of inv(14) in T cell clones, established from patients with ataxia telangiectasia, lies outside the immunoglobulin heavy chain gene locus on 14q32.3, and more proximal to the centromere than the distal breakpoint of inv(14) in the T cell lymphoma cell line SUP-T1. We report 3 cases of T cell lymphoma cytogenetically showing the same type of inv(14) as the AT T cell clones. All 3 cases express a similar immunophenotype, which is that of peripheral T lymphocytes with phenotypic remnants of thymic or postthymic lymphoblasts. This finding provides evidence that this type of inv(14) is involved in the malignant transformation of mature T lymphocytes.     

The chromosome breakpoint at 14q32 in an ataxia telangiectasia t(14;14) T cell clone is different from the 14q32 breakpoint in Burkitts and an inv(14) T cell lymphoma

Summary The T cell receptor chain gene locus and the immunoglobulin heavy chain gene locus (IgH) have previously been mapped to the q11 and q32 positions respectively of the human chromosome 14. Both of these sites are also common breakpoints in lymphocytes from ataxia telangiectasia (A-T) patients. Using in situ hybridisation we show that the 14q32 breakpoint in an A-t non-leukaemic T cell clone with t(14;14) translocation, lies outside the IgH locus and proximal to it with respect to the centromere. The 14q11-14qter segment of the homologous chromosome 14 carrying the constant gene region of the chain locus is translocated to this 14q32 position.     

Isolation of a polymorphic genomic clone from chromosome 7

Summary A peptide prepared from purified factor 13B (F13B) was sequenced, and a single, long oligonucleotide corresponding to its cognate DNA sequence was constructed and used to screen a chromosome 7 specific genomic library. The positive clone isolated, designated pKV13, was only related to F13B at the oligonucleotide region, but has proved to be a valuable chromosome 7 marker. pKV13 maps to 7pter-q22 in hybrid cell lines, and is present in a chromosome-mediated gene transfer (CMGT) cell line that also contains met and other 7q probes. pKV13 defines a common MspI restriction fragment length polymorphism (RFLP), and is genetically linked to two markers on the long arm of chromosome 7, B79a and COL1A2, both themselves linked to the cystic fibrosis locus. Multipoint linkage analysis demonstrates that KV13 maps centromeric to both B79a and COLIA2. pKV13 has been used to demonstrate the existence of rearrangements within CMGT hybrisd, and will also prove valuable in multipoint linkage studies of other 7q markers. Finally, pKV13 provides a new polymorphic locus for the characterisation of 7q deletions in myeloid disorders such as myelodysplastic syndrome.     

Identification of a 4A/7R and a 7B/4R wheat-rye chromosome translocation

Summary By producing chromosome substitutions with Imperial rye chromosomes 4R (C) and 7R (D) in the wheat cultivar Chinese Spring two spontaneous translocation lines were obtained. One involves segments of wheat chromosome 4A and rye chromosome 7R, the other involves portions of wheat chromosome 7B and rye chromosome 4R     

Proximal trisomy 13q and distal monosomy 8p in a dysmorphic and mentally retarded patient with an isodicentric chromosome 13q and a 13q/8p translocation chromosome

A 40 year-old dysmorphic and mentally retarded female is reported with a de novo unbalanced chromosomal rearrangement (karyotype: 46,XX,der(8)t(8;13)(p23;q123),idic(13)(pter-->q123: q123-->pter) resulting in an isodicentric chromosome 13 and a double aneusomy including partial trisomy 13 (13pter-q123) and distal monosomy 8p (8pter-p23). The main clinical findings consist of developmental/mental retardation, behavioural disturbances and minor congenital defects, not consistent with the clinical pattern of either of the two aneusomies. A mechanism for the chromosome rearrangement is proposed and the absence of specific physical findings in the present patient is discussed in the light of the available literature data.     

Transmission of a t(13q22q) chromosome observed in three generations with segregation of the translocation D1-trisomy syndrome.

A case of an inherited type of D/G translocation D1-trisomy syndrome was described. A female proposita who had the clinical signs of D1-trisomy syndrome was found to have a chromosome complement of 46,XX,--G,+t(DqGq). examination of Q- and G-stained karyotypes revealed that the chromosomes involved in the translocation were members of Nos. 13 and 22, or t(13q22q) with breaks at p12 of both chromosomes. C-stained figures also showed a large heterochromatin block in its centromeric region. The t(13q22q) chromosome was transmitted from the paternal grandmother of the proposita through at least three generations.     

Analysis of chromosome 21 yeast artificial chromosome (YAC) clones.

Chromosome 21 contains genes relevant to several important diseases. Yeast artificial chromosome (YAC) clones, because they span > 100 kbp, will provide attractive material for initiating searches for such genes. Twenty-two YAC clones, each of which maps to a region of potential relevance either to aspects of the Down syndrome phenotype or to one of the other chromosome 21-associated genetic diseases, have been analyzed in detail. Clones total approximately 6,000 kb and derive from all parts of the long arm. Rare restriction-site maps have been constructed for each clone and have been used to determine regional variations in clonability, methylation frequency, CpG island density, and CpG island frequency versus gene density. This information will be useful for the isolation and mapping of new genes to chromosome 21 and for walking in YAC libraries.