Mapping of the 8q23 translocation breakpoint of t(8;13) observed in a patient with multiple exostoses

A detailed cytogenetic map was constructed around the chromosomal breakpoint of t(8;13) observed in a patient with multiple exostoses. The order of seven loci defined by cosmid clones mapped to 8q23 was determined by means of two-color fluorescence in situ hybridization (FISH) on elongated prophase chromosomes, and localizations of these markers relative to the breakpoint were examined. The results indicated that loci defined by cC18-553 and cC18-1512 flank the breakpoint. By pulsed-field gel electrophoresis of DNA digested with BssH11 and Southern hybridization with cC18-1512, DNA from the patient showed a band which was not observed in DNA isolated from either parent. As the normal size of this BssH11 fragment is 600 kb, the chromosomal breakpoint probably lies less than 600 kb away from cC18-1512. Genes Chrom Cancer 9:57-61 (1994). © 1994 Wiley-Liss, Inc.     

Reciprocal translocation associated with multiple exostoses in seven members of a three generation family and discovered through an infertile male

We report a four generations family with multiple exostoses segregating with a reciprocal translocation t(8;19)(q24.11;q13.13) in 8 members of three generations. FISH investigations detected a breakage of the dosage-sensitive EXT1 gene. Although three members of the family died perinatally from unknown causes and one carrier had four spontaneous abortions, the translocation was discovered only when the cytogenetic analysis was requested in an affected male because of oligozoospermia. In fact, it is well known that infertile males may be carriers of reciprocal or Robertsonian translocations with a higher frequency than the general population. This family stresses the importance of requesting the cytogenetic analysis in all cases in which a dominant disease segregates with repeated miscarriages and/or newborn deaths of unknown cause.     

Childhood acute lymphoblastic leukemia associated with an unusual 8;14 translocation

An elderly woman had dysmyelopoietic syndrome with a rapidly fatal course. On initial marrow and unstimulated blood cell examination a structural anomaly of the X chromosome was observed with a 46,X,idic(X)(q13) karyotype with the exception of two cells showing a 47,XXX karyotype. Peripheral blood lymphocytes showed a normal 46,XX karyotype. The specificity of these findings is discussed.     

Linkage analysis of polymorphisms within the DNA fragment XJ cloned from the breakpoint of an X;21 translocation associated with X linked muscular dystrophy.

Cloning of a DNA segment including the translocation breakpoint in a female with an X;21 translocation and X linked muscular dystrophy has led to identification of three subclones which detect polymorphic markers. The alleles of these markers, XJ1 X 1, XJ1 X 2, and XJ2 X 2, are in strong linkage disequilibrium. Linkage analysis in 31 families with Duchenne or Becker muscular dystrophy has shown recombination within the XJ segment in one case, and recombination of DMD with both the XJ segment and the pERT87 segment in a second, but has revealed no recombination between the XJ and pERT87 segments. The XJ markers increase the proportion of DMD and BMD families that are informative for carrier detection and prenatal diagnosis, but in view of the risk of recombination they must be used with caution. The site(s) of the DMD mutation(s) relative to the XJ and pERT87 markers, and the detailed molecular structure of the DMD region, remain to be determined.     

The gene for hereditary multiple exostoses does not map to the Langer-Giedion region (8q23-q24).

Hereditary multiple exostoses is a dominantly inherited skeletal disorder which alters enchondral bone during growth and is characterised by exostoses of the juxta-epiphyseal regions. Using polymorphic DNA probes, we have been able to exclude the disease gene from close proximity to the 8q24.1 region where a dominant syndrome with multiple exostoses, the trichorhinophalangeal syndrome type II (TRP II, Langer-Giedion syndrome, MIM 15025), has been previously localised (pairwise linkage Z = -8.96 at theta = 0 with probe L48 at locus D8S51). Multipoint linkage analysis using probes L48, L24, and L1 consistently excluded the HME gene from a large area of the distal long arm of chromosome 8, spanning the smallest region of overlap assigned to the TRP II gene. These studies support the clinical view that HME and TRP II are distinct entities.     

De novo X;Y translocation associated with imperforate anus and retinal pigmentary abnormalities

Cytogenetically detectable translocations of Y chromosome material onto the distal short arm of an X chromosome are rare and result in a variable and poorly defined phenotype of short stature and short limbs occasionally associated with mental retardation. We report on a patient with a de novo 46,X,t(X;Y)(p22;q11) chromosome constitution who has additional features not previously described with this chromosome abnormality, including abnormal retinal pigmentation, imperforate anus, and hydronephrosis. Our patient extends the phenotype associated with X;Y translocations, raising new considerations for the clinical management and genetic counseling of such patients and their families.     

Gonadal dysgenesis in a patient with an X;3 translocation: case report and review.

A patient with primary amenorrhoea and absence of secondary sex characteristics was found to have a balanced X;3 translocation. This phenotype is reported in approximately one-third of the balanced X;autosome translocation cases. The normal X chromosome is inactive in the present case which is in agreement with most of the similar cases. A review of the 66 balanced X;autosome translocations reported to date is presented.     

Multiple skeletal familial abnormalities associated with balanced reciprocal translocation 2;8(q32;p13)

A father and three of his offspring had skeletal abnormalities consisting of a short forearm, cubitus valgus, fusion of first and second cervical vertebrae, and cleft of L5 and SI. All four had a reciprocal, apparently balanced, translocation 2;8(q32;p13). Normal sibs had normal chromosomes. We conclude that this may be a rare instance of an autosomal dominant condition associated with a balanced chromosome translocation.     

An (8;14)(q24;q11) translocation involving the T-cell receptor alpha-chain gene and the MYC oncogene 3' region in a B-cell lymphoma

We describe a t(8;14)(q24;q11) involving the T-cell receptor alpha-chain gene (TCRA) and the 3' region of the MYC protooncogene in a B-cell lymphoma. The B-cell origin of this tumor was determined by its histological architecture, by immunophenotypic analysis, and by Southern analysis of immunoglobulin gene rearrangements. An identical fragment encompassing the translocation breakpoint junction was detected through Southern analysis using both a TCRAJ and a MYC probe. The other alleles at the TCRAJ and MYC loci were in the germline configuration. Restriction enzyme and nucleotide sequencing analyses revealed that the breakpoint junction on chromosome 8 lies approximately 700 base pairs (bp) downstream of the 3' end of the third MYC exon; on chromosome 14, the break is located 12.6 kilobases (kb) downstream of the 3' end of the C delta fourth exon. A heptamer-like consensus sequence on chromosome 14 adjacent to the translocation breakpoint implies the involvement of recombinase activity. However, no consensus sequences were found on chromosome 8 within 140 bp in either direction from the breakpoint. It is possible that this translocation involving MYC occurred during an attempt at an inappropriate rearrangement of the TCRA locus in a cell of B-cell lineage.     

A fetus with an X;1 balanced reciprocal translocation and eye disease.

A 19 week female fetus is described with a de novo X;1 reciprocal balanced translocation, with the breakpoint on the X chromosome at Xp11.4, and eye pathology consistent with the early stages of Norrie disease. The fetus seems to be an example of a female manifesting an X linked recessive disease, and it was shown that the normal X chromosome was completely inactivated in all cells examined. Norrie disease has been mapped to Xp11.3, and fluorescence in situ hybridisation studies showed that the Norrie disease gene had not obviously been disrupted. Mutation screening by SSCP analysis showed no aberrant fragments of the coding region of the gene. Several eye disease genes map to the same region of the X chromosome, but are excluded on grounds of pathology. One possibility is that this fetus has a Norrie-like eye disease caused by the mutation of another gene located at Xp11.4. If this is so, there are implications for prenatal diagnosis.     

Two brothers with an unbalanced 8;17 translocation and infantile pyloric stenosis

Two half-brothers are described who had developmental delay and minor dysmorphic features, both of whom had operative treatment for pyloric stenosis. They had identical unbalanced karyotypes: 46,XY,-17,+der(17)t(8;17) (q24;q25). This was inherited from their mother who had the balanced form of the translocation. She was of normal intelligence and had no history of pyloric stenosis herself or in her extended family. It is suggested that the unbalanced chromosomal rearrangement could have been associated with the development of pyloric stenosis in these two brothers.     

X;14 translocation:an exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14)(q22;q24.3) in all her cells and a small interstitial deletion of band 15q112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis

A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 × 10⁻⁴, odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 × 10⁻⁹, OR 0.77) was shown.     

Localization of the 8;13 translocation breakpoint associated with myeloproliferative disease to a 1.5 mbp region of chromosome 13

There are five reported cases of an atypical myeloproliferative disorder in which the leukemia cells have a consistent t(8;13)(p11;q12) translocation. We analyzed the breakpoint in metaphases from two of these patients by fluorescence in situ hybridization using a series of yeast artificial chromosomes (YACs) derived from the 13q12 region. We found that a YAC containing the FLT1 and FLT3 oncogenes was localized distal to the 13q12 breakpoint and was not rearranged. YAC 66, a YAC that lies immediately adjacent to the chromosome 13 centromere, was localized proximal to the 13q12 breakpoint and was not rearranged. A third YAC, which is located between FLT1 and YAC 66, was unrearranged in normal metaphase chromosomes, but showed hybridization signals on both derivative chromosomes in both cases. Thus, the breakpoints in these two cases are localized to the same 1.5 Mbp region of 13q12. This may be the site of an unidentified gene involved in the pathogenesis of some types of leukemia.