In the present study, we investigated the associations of polymorphisms in cytochrome P450 gene (CYP1A1), glutathione S-transferase genes (GSTM1 and GSTT1) with chronic myelogenous leukemia (CML). A total of 126 patients with CML and 172 healthy volunteers were genotyped, and the DNA was isolated from their blood samples. The polymorphisms were assessed by polymerase chain reaction (PCR) restriction fragment length polymorphism-based methods and multiplex PCR. Logistic regression analyses showed significant risk of CML associated with CYP1A1 Val allele [odds ratio (OR) 3.3, 95% confidence intervals (CI) 1.96-5.53], (p < 0.0001) while CYP1A1 Val/Val homozygotes were observed only in the CML patients. There was statistically significant difference in the frequency of GSTM1 and GSTT1 null genotypes. The GSTT1-null genotype was slightly higher in 27% of CML cases and 16.7% of controls (OR 1.98, 95% CI 1.12-3.5) (p < 0.020). The GSTM1 null was higher in 42.8% of CML cases and 22.7% of controls (OR 2.55, 95% CI 1.54-4.22) (p < 0.00024). The individuals carrying CYP1A1 Ile/Val (AG) and GSTM1 null genotype have 9.9 times higher risk to be CML than those carrying CYP1A1 Ile/Ile (AA) and GSTM1 present genotype (OR 9.9, 95% CI 2.7-36.3) (p < 0.0001). This suggests that the association of the GSTM1 null genotype, either alone or in combination with GSTT1 null, with CYP1AI heterozygous leads to the CML risk.

Infertility is an important health issue affecting numerous couples. Approximately 30-50% of the cases of male infertility is due to unknown reasons. The main genetic factors involved in male infertility are chromosomal abnormalities and Y chromosome microdeletions within the Yq11 region. The genes controlling spermatogenesis located in the Yq11 region are termed azoospermia factor genes (AZF). Klinefelter syndrome (KS) is the most common of the chromosomal anomalies in the infertile male. AZF microdeletions on the Y chromosome are the most frequent genetic cause of male infertility. Screening for microdeletions in the AZFa, b and c regions of the Y chromosome showed a marked variation among different studies. The present study aimed to investigate the prevalence of such deletions in Syrian men. A total of 162 infertile males (97 azoospermic, 49 oligospermic and 16 severely oligospermic) were screened for chromosomal abnormalities and Y chromosome microdeletions using 28 markers in the AZF region. Twenty (12.34%) patients had chromosomal rearrangements, 17 of them showed sex chromosome abnormalities (11 of 17 patients within the azoospermic group had a KS of 64.7%), 2 patients had apparently balanced autosomal rearrangements, while 1 patient had an inversion. Of the 162 infertile men, 46 patients (28.4%) had Y chromosome microdeletions within the AZF-regions. Most frequently hit were the AZFc (34.8%), followed by the AZFbc, AZFa, AZFac, AZFbc, AZFb, AZFd, AZFab, AZFad, AZFbd, AZFabc and the AZFbcd. Combined AZF deletions involving three regions with chromosomal abnormalities were observed in one case. The higher frequency of AZF deletions in our study was comparable with frequencies in other countries and regions of the world, possibly due to the elevated number of the sequence-tagged site (STS) markers used for this screening.

Abnormalities involving sex chromosomes account for approximately 0.5% of live births. The phenotypes of individuals with mosaic cell lines that exhibit structural aberrations of the X and Y chromosomes are variable and difficult to predict. Phenotypes associated with sex chromosome mosaicism vary from females with Turner syndrome to males with infertility, and include individuals with ambiguous genitalia. In this study, we report a 17-year-old male with phenotypic features of Klinefelter syndrome with an isodicentric Y chromosome and a final karyotype of 45,X[4]/46,X,idic(Y)(q11.21)[95]/47,XX,+idic(Y)(q11.21)[1]. Application of high resolution molecular cytogenetic techniques as well as molecular studies revealed two copies of the sex-determining region of Y chromosome (SRY) gene and two centromers. Additionally, the breakpoint in Yq11.21 was narrowed down between positions 13.4 and 14.3 MB (hg18). We present a patient with partial disomy of Ypter to Yq11.21 in the majority of the patient cells, showing phenotypic features of Klinefelter syndrome. The syndrome may have occurred due to a more prominent presence of the cell line 47,XX,+idic(Y)(q11.21) detected only once in 1% of the peripheral blood cells. This finding may prove helpful in similar cases with symptoms of Klinefelter syndrome, but which exhibit an absence of the cell line 47,XXY in peripheral blood.

Abstract. autosomal recessive non-syndromic hearing impairment (arnSHi) is caused by mutations in the gap junction gene GJB2 (connexin 26; cx26) in numerous human populations. The aim of this study was to determine the frequency of six GJB2 mutations in 50 Syrian families with congenital deafness and in 180 controls. Pcr-rFlP was used to detect the 35delG, 167delT, M34T, W24X, W77r and e47X mutations, and direct sequencing was performed for the 35delG mutation. The data revealed a high prevalence of the 35delG mutation among deaf families. Homozygous 35delG was detected in fifteen of the Syrian families (30%). a compound heterozygous genotype was observed in two families: one with the 35delG/167delT mutation (2%) and one with the 35delG/M34T mutation (2%). Nine families were heterozygous with no second identified mutation in Cx26: four with 35delG+/unknown (8%), four with 167delT/unknown (8%) and one with M34T/unknown (2%). The W24X, W77R and e47X mutations were not detected in any of the study subjects. Three individuals with the heterozygous 35delG genotype (1.66%) and five with the heterozygous 167delT genotype (2.77%) were detected among the controls. No other mutations were found among the controls. These results have important implications for the diagnosis and counseling of families with cx26 deafness.

BackgroundPartial trisomy of the short arm of chromosome 9 is among the most common autosomal structural chromosomal anomalies leading to chromosomal imbalance in human. Clinical characteristics are craniofacial dysmorphism including hypertelorism, prominent nose, deep-set eyes, and down-slanting palpebral fissures. The degree of clinical severity in partial trisomy 9p roughly correlates with the size of the chromosomal imbalance. Therefore, breakpoints as well as clinical findings need to be precisely defined for differential diagnosis.ResultsChromosomes of a young female were analyzed due to primary amenorrhea, short stature, developmental delay and a characteristic facial appearance. Cytogenetic analysis using GTG banding identified a karyotype 46, XX, add(9pter). Surprisingly the application of high resolution molecular cytogenetic techniques characterized a partial trisomy 9p24.2-p22 and partial monosomy 9pter-p24.2. To the best of our knowledge only four similar case were reported by now.ConclusionAttempts for genotype-phenotype correlations for partial trisomy 9p might have been hampered by the fact that more complex, cryptic aberrations were neither considered nor detected in comparable clinical cases.

C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR) gene was a risk factor for recurrent pregnancy loss (RPL), but few studies have confirmed a possible role of MTHFR A1298C polymorphism in RPL risk. This study was carried out to determine the influence of the MTHFR gene polymorphisms in RPL Syrian women. A case-control study was performed on 2 groups (106 healthy and 100 RPL women). The frequency of the MTHFR gene polymorphisms was determined by polymerase chain reaction based on restriction fragment length gene polymorphism. In the RPL group, the genotype frequencies of MTHFR C677T were CC (41%), CT (41%), and TT (18%), and in the control group, the frequencies were CC (62.2%), CT (36.7%), and TT (1%). Statistical analysis showed a homozygous TT genotype and T allele were significantly different in the RPL group ( P = .000003 and P = .000019, respectively). The genotype frequencies of MTHFR A1298C were AA (53%), AC (44%), and CC (8%) in the RPL group, whereas in the control group, these were AA (61.3%), AC (37.8%), and CC (1%). A significant difference in the CC genotype and C allelic frequencies in the RPL women was observed ( P = .014 and P = .064, respectively). The patients having compound heterozygous (677 CT/1298AC) were associated with an estimated 4.86-fold increase in risk of pregnancy loss compared to individuals with a wild type ( P = .012). Our findings indicate that RPL women with homozygous genotype for (C677T and A1298C) either alone or compound heterozygous genotypes have a high risk of pregnancy loss in Syrian women.

The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. Amplification or duplication of the BCR-ABL gene has been found to be one of the key factors leading to drug resistance to imatinib mesylate (IM). In the present study, we identified the presence of isodicentric Ph chromosomes [idic(Ph)] in an IM-resistant patient. Fluorescence in situ hybridization (FISH) analysis on metaphase chromosomes confirmed the heterogeneity and amplification of the fused BCR-ABL gene. FISH analysis superimposed on G-banding confirmed the presence of idic(Ph) chromosomes. Reverse transcription-polymerase chain reaction (RT-PCR) products revealed the presence of the BCR-ABL fusion transcript b3a2. The idic(Ph) chromosomes in CML were shown to be fused at the satellite regions of the short arms. The patient did not respond to IM chemotherapy and did not achieve remission. In this study, the impact of the idic(Ph) chromosomes on genomic instability, heterogeneity and amplification of the BCR-ABL gene in IM-resistant patients is discussed.

BackgroundThe so-called Philadelphia (Ph) chromosome is present in almost all cases with chronic myeloid leukemia (CML). Around 5-10% of these patients show complex translocations involving other chromosomes in addition to and/or besides chromosomes 9 and 22. As nowadays most CML cases are treated with Imatinib, variant rearrangements have in general no specific prognostic significance, though events of therapy resistance remain to be studied.ResultsHere we report a Ph chromosome positive patient with hematological typical chronic phase CML. Untypically, an unbalanced complex rearrangement involving chromosomes 16 and 17 leading to a deletion of 16pter and partial trisomy of 17q21 to 17qter, was identified besides a trisomy 8 and an additional Ph chromosome in a part of malignant cells.ConclusionHere a novel and cytogenetically unique case of a Ph chromosome positive CML clinically in chronic phase is reported, having complex secondary chromosomal aberrations. Thus, CML patients with complex chromosomal changes are nonetheless treatable by Imatinib.