Cytogenomic characterization of 1q43q44 deletion associated with 4q32.1q35.2 duplication and phenotype correlation.

BACKGROUND: Microdeletion of 1q43q44 causes a syndrome characterized by intellectual disability (ID), speech delay, seizures, microcephaly (MIC), corpus callosum abnormalities (CCA) and characteristic facial features. Duplication of 4q is presented with minor to severe ID, MIC and facial dysmorphism. We aimed to verify the correlation between genotype/phenotype in a patient with 1q43q44 deletion associated with 4q32.1q35.2 duplication. CASE PRESENTATION: We report on a 3 year-old female patient with delayed motor and mental milestones, MIC and facial dysmorphism. She is a child of non-consanguineous parents and no similarly affected family members. CT brain showed abnormal gyral patterns, hypogenesis of corpus callosum and bilateral deep Sylvian fissure. Electroencephalogram showed frontotemporal epileptogenic focus. Her karyotype was revealed as 46,XX,add(1)(q44). Fluorescence in situ hybridization (FISH) using whole chromosome paint (WCP1) and subtelomere 1q revealed that the add segment was not derived from chromosome 1 and there was the deletion of subtelomere 1q. Multiple ligation probe amplification (MLPA) subtelomere kit revealed the deletion of 1q and duplication of 4q. Array CGH demonstrated the 6.5 Mb deletion of 1q and 31 Mb duplication of chromosome 4q. CONCLUSION: The phenotype of our patient mainly reflects the effects of haploinsufficiency of AKT3, HNRNPU, ZBTB18 genes associated with duplication of GLRA3, GMP6A, HAND2 genes. Patients presented with ID, seizures, MIC together with CCA are candidates for prediction of 1q43q44 microdeletion and cytogenomic analysis.

Clinical significance of telomerase genes (hTERC and hTERT) amplification in patients with acute myeloid leukemia.

UNLABELLED: Acute myeloid leukemia (AML) describes a heterogenous group of hematological disorders. Cytogenetic and molecular assays have allowed patients' follow up aiming for detection of minimal residual disease, prediction of patients' outcome, in addition to providing the rationale for designing novel molecular-targeted therapeutic strategies. Human telomerase reverse transcriptase (hTERT), encoded by the hTERT gene and the telomerase RNA component (hTERC) genes are frequently amplified in human tumors, which may indicate that the hTERT and the hTERC genes may be target for amplification during the transformation of human malignancies including hematological malignancies. This genetic event has implications in diagnosis, prognosis and therapeutics of cancer. To evaluate the hTERC and hTERT genes as a prognostic marker in patients with AML, hTERC and hTERT gene amplification was studied in 20 adult AML patients using a commercial FISH probes (Kreatech) designated to detect the copy numbers of the genes. They were 12 males and 8 females. Their ages ranged from 16 to 67 years. The patients were further divided into two groups; group I (12 patients) includes newly diagnosed AML patients and group II (8 patients) includes patients taken at 28th day of chemotherapy. The hTERC amplification was detected in 19/21 cases (90.5%). The copy number of the gene ranged from 2-5 copies per interphase cell. For the hTERT gene, the amplification was found in the same percent of the patients. The copy number of the gene ranged from 2-9 copies per interphase cell. On comparing the group I with group II there was a highly statistical significant difference regarding the percent of amplification of both genes. The percent of amplification of hTERT gene was found to be higher among patients with poor outcome of the disease than in patients with good outcome. On the contrary the hTERC gene amplification did not exhibit such a correlation. In conclusion, hTERT and hTERC genes amplification were detected in patients with AML; therefore telomerase can be a good cancer marker which may be involved in carcinogenesis of leukemia. Higher amplification was found in de novo cases than cases in remission which emphasize its role in clinical analysis, disease monitoring and detection of minimal residual disease. KEYWORDS: Acute Myeloid leukemia, telomerase amplification, hTERC gene, hTERT gene.

Role of ginger against the reproductive toxicity of aluminium chloride in albino male rats.

The aim of the current study was to evaluate reproductive disorders concomitant with aluminium chloride (AlCl(3) ) toxicity in Albino male rats. Attention was also directed to study the protective influence of ginger against this toxicity. Forty-five mature Albino Wistar male rats were equally divided into three groups; the first group was served as control group while those of the second group (AlCl(3) ) were daily treated with 34 mg/kg bw. AlCl(3) orally. The third group (AlCl(3) + ginger) was treated daily with AlCl(3) as in group 2 in combination with ginger (40 mg/kg bw), which started 2 weeks prior to AlCl(3) . Five animals from each group were sacrificed on days 30, 45 and 60 of treatment. AlCl(3) administration significantly decreased serum testosterone levels, increased testicular homogenate malondialdehyde and deteriorated semen picture with increased testicular DNA fragmentation. Histopathological examination revealed degenerative changes of the seminiferous tubules with focal areas of necrosed spermatogenic cells, marked degeneration and desquamation of the lining epithelial cells of epididymis as well as multiple calcified material in prostate gland following 60 days of aluminium treatment. Ginger treatment started to improve significantly all studied parameters after 60 days as compared with AlCl(3) -treated group. In the current study, it was concluded that AlCl(3) had a destructive effect on all the studied reproductive parameters. Treatment with ginger has an ameliorating effect against AlCl(3) toxicity after 60 days post-treatment.

Partial trisomy of the distal part of 10q: a report of two Egyptian cases.

Partial trisomy of the distal third of the long arm of chromosome 10 is a well defined but rare syndrome. Most cases result from an unbalanced translocation. Growth retardation, developmental delay and characteristic dysmorphic features are well described in the syndrome. This report includes 2 Egyptian cases with partial 10q trisomy involving different breakpoints. Cases were subjected to full clinical examination and detailed cytogenetic analysis using conventional and FISH studies. Results showed that the karyotype of case 1 was 46,XX,der(7)t(7;10)(p22;q23).ish(wcp7+;wcpl0+) and the karyotype of case 2 was 46,XX,der(7)t(7;10)(p22;q25).ish(wcp7+;wcp 10+). The chromosomal abnormalities in case 1 resulted from a paternal balanced translocation while case 2 resulted from a maternal balanced translocation involving chromosomes 10 and 7 in both cases. The probands' phenotypes were correlated to the breakpoints and compared to previously reported cases with partial trisomy 10q. Both cases had the well characterized phenotype of the distal trisomy of 10q in the form of mental retardation, microcephaly, characteristic dysmorphic facies and limb anomalies as trisomy in both cases involved the 10q25-->qter region. However, case 1 with 10q23-->qter duplication showed more severe clinical manifestations than case 2 with less extensive 10q25-->qter trisomy. These included severe failure to thrive, cardiac involvement and death from respiratory and heart failure. This study confirmed that unbalanced chromosome regions of the long arm of chromosome 10 play an important role in developmental malformations and that a more severe form is associated with involvement of 10q23. It also emphasizes the importance of increasing public awareness regarding these chromosomal rearrangements and the importance of genetic counseling and prenatal diagnosis to avoid recurrences and associated family stress. This was clearly demonstrated in the second family in this study as the couple refused any follow up or further investigations due to religious beliefs despite their social and educational level.

Phenotypic and cytogenetic spectrum of 9p trisomy.

Trisomy 9p is one of the most frequent autosomal anomalies compatible with long survival rate. The spectrum of clinical severity in trisomy 9 roughly correlates with the extent of trisomic chromosome material. Trisomy 9p is a clinically well delineated syndrome and of all stigmata craniofacial dysmorphism is most specific. In this study we report five cases with de novo trisomy 9p. The study aimed at the identification of the genotype/phenotype correlations in patients with different breakpoints. GTG banding, DAPI stain, whole chromosome paint, centromere, telomere and 9p21 specific locus probes demonstrated that partial trisomy 9p in case 1 was due to isochromosome 9p with translocation of the long arm of re-arranged chromosome 9 onto the short arm of chromosome 13, cases 2 and 3 had intrachromosomal duplication of the short arm of chromosome 9 [dup(9)(p21p24)], case 4 had "classical" 9p trisomy and case 5 had duplication of whole short arm and part of the long arm of chromosome 9 (partial 9 trisomy). Although cases 1 to 4 had trisomy involving 9p, cases 1 and 2 exhibited the classical clinical manifestations of 9p trisomy, while cases 3 and 4 had additional features overlapping with Coffin-Siris syndrome. The present study strengthens the association of Coffin-Siris syndrome and 9p, the significance of such observations may point to possible gene location of Coffin-Siris syndrome on 9p. Case 5 had additional manifestations more than those typical of trisomy 9p which could be due to duplication of 9q21 region. Wide gap between 1st and 2nd toes, observed in the studied cases, can be added to the phenotype of this trisomy. Three of our cases had brain malformations, case 3 had dilated ventricles with hypogenesis of corpus callosum, case 4 had agenesis of corpus callosum, and case 5 had Dandy-Walker malformation. We also suggest that dosage effects of genes located in 9pter-q22 contribute to the etiology of Dandy-Walker syndrome. We recommend MRI studies as a routine in all cases with trisomy 9p.

Roberts syndrome: study of 4 new Rgyptian cases with comparison of clinical and cytogenetic findings.

Roberts syndrome is a rare autosomal recessive genetic disorder (MIM 268300). It is characterized by pre and postnatal growth retardation, severe shortening of limbs with radial defects, oligodactyly and characteristic facial features. The present study reports 4 new cases of Roberts syndrome from 3 families presenting variable phenotypes. Patients were thoroughly investigated clinically and cytogenetically. By reviewing literature, we compared our cases to those previously reported. The rating severity system proposed by Van den Berg and Francke (30) was applied to correlate the phenotypic and cytogenetics changes. We observed more severe reduction defects in the upper limbs than in the lower limbs. While the main reduction defects in the upper limbs involved the thumb and radius ranging to phocomelia, absent or severely hypoplastic fibula was the main lower limb involvement. We emphasize this finding in the present investigation. Heterochromatin repulsion of chromosomes derived from Roberts syndrome patients is a characteristic cytogenetic abnormality. It was a constant finding in our studied patients demonstrated by DABI stain which supports the possibility that mutations in Roberts syndrome lie in centromere related proteins which may also play a role in body patterning. This was proved recently by Vega et al. (31). Application of the clinical rating score and its correlation with cytogenetic changes showed negative results. Cytogenetic studies in normal obligatory heterozygotes parents showed no changes. Phenotypic variability within the same family as well as between different families was observed. The ascertainment of 4 cases with Roberts syndrome from 3 Egyptian consanguineous families during one year in our department may indicate a high frequency of the Roberts syndrome allele among Egyptians. This confirms the need for molecular studies for early and accurate prenatal diagnosis to prevent such dramatic malformation syndrome.