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The existence of parent of origin differences in the expression of some genes, a process known as genomic imprinting, has been recognised and documented over the past several years. This epigenetic marking process results in the differential expression of normal genes, depending on whether they are of maternal or paternal origin. A number of human disorders have been identified as resulting from alterations in genomic imprinting.1 One type of genetic abnormality which can unmask genomic imprinting is uniparental disomy (UPD), in which both chromosomes of one pair are inherited from one parent, with no contribution from the other.2 Distinct phenotypes exhibited by patients with maternal and paternal UPD(14) strongly suggest that at least some genes on human chromosome 14 are subject to imprinting effects.3-6 This finding is supported by studies in the mouse indicating that the distal portion of chromosome 12, recognised as a candidate imprinted region, is syntenic with human chromosome 14q.7 Nevertheless, no imprinted genes have yet been identified on chromosome 14, and the location of the imprinted region on human chromosome 14 remains unclear. Analysis of parental origin effects in human trisomy for chromosome 14q8 or monosomy for the same chromosome9makes the region 14q23-q32 a candidate region for containing imprinted genes.10 Moreover, the observation of a partial duplication of 14q in a developmentally delayed girl with minor abnormalities and her phenotypically normal father led Robin et al 11 to propose that the 14q24.3-q31 region may be imprinted. As genotype-phenotype correlations in patients with aneusomy for this region may help the identification of imprinted genes on human chromosome 14, we report here a direct 14q31 duplication observed in a child with mild developmental delay and his phenotypically normal mother. This duplication was also detected in five relatives with a normal …

We report the cases of two unrelated patients with psychomotor retardation and craniofacial abnormalities, in whom cytogenetic studies have revealed a terminal deletion of chromosome 13 confirmed by fluorescence in situ hybridization (FISH). This del(13)(q33.2) is the smallest terminal deletion of the 13q reported so far. Interestingly enough, the serum level of coagulation factors VII and X, whose genes are located in 13q34, were reduced in both patients. These cases illustrate the difficulties in identifying precisely chromosome deletions and demonstrate that FISH techniques allow to obtain a more precise correlation between clinical phenotype and cytogenetic abnormalities.

Two patients with Philadelphia-positive chronic myelogenous leukemia underwent allogeneic bone marrow transplantation from a related HLA mismatched donor (patient 1) or from an unrelated HLA-identical donor (patient 2). Following bone marrow transplantation partial engraftment (patient 1) or graft failure (patient 2) occurred followed by autologous Philadelphia negative hematopoietic recovery either spontaneously (patient 1) or after infusion of autologous bone marrow rescue (patient 2). Neither Philadelphia chromosome, nor bcr-abl rearrangement was detectable by PCR analysis up to 7 years (patient 1) and 9 years (patient 2) post-transplantation. These two observations indicate that sustained engraftment of allogeneic bone marrow stem cells following a myeloablative regimen is not necessary to cure chronic myelogenous leukemia. It is hypothesized that the proliferative advantage of Philadelphia-negative progenitors and the anti-leukemic effect of lymphocytes in the graft have resulted in prolonged remission of the patients.

International audience; A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.

The polymerase chain reaction (PCR) was used to amplify cDNA in order to characterize normal and hybrid T-cell receptor (TCR) gene rearrangements derived from a T-cell acute lymphoblastic leukemia (T-ALL) bearing a chromosome 7 inversion. The nucleotide sequence analysis of the amplified product showed the presence of an out-of-frame V beta/J gamma/C gamma transcript and an in-frame V gamma/J gamma/C beta transcript which result from an interlocus recombination between the TCR-beta and gamma loci and the transcription of the reciprocal hybrid TCR gene. The sequence analysis of the reciprocal DNA segment directly involved in the breakpoint of the inversion showed a recombination between a J gamma-sequence heptamer signal and a coding J beta gene segment. The exonuclease nibbling of each DNA extremity and the non-templated nucleotide insertion observed at both coding and reciprocal joints demonstrate that the inversion is mediated by the lymphocyte recombinase complex. During T-cell differentiation, TCR-beta genes are rearranged prior to TCR-alpha genes. In the present case of T-ALL, we have shown that TCR-delta genes are rearranged at both loci, excluding productive rearrangements of TCR-alpha genes. The molecular analysis of the normal TCR genes derived from the leukemic cells revealed the presence of productively rearranged TCR-beta, gamma, and delta genes. Cell surface staining of these cells showed the presence of CD3 molecules and of a TCR-beta chain corresponding to the normal beta allele expressed in a disulfide-linked complex with a protein which is not TCR-alpha, gamma, or delta. This could represent the cell surface expression of the hybrid TCR-V gamma/C beta protein or the expression of a TCR-beta homodimer.