Pericentric inversion chromosome 9: problem and significance in clinical genetics

Pericentric inversions of chromosome 9 are among the most frequent chromosomal rearrangement in human. It has generally been considered as a normal variant rather than an abnormal karyotype. Howe ver, many reports in the recent literature link pericentric inversions of chromosome 9 with infertility, recurrent abortions, and a number of other abnormal clinical conditions. Therefore, in order to clarify if inv[9] is harmful or benign we analyzed the frequency and clinical significance of inv[9] in patients with various genetic disorders over a 3-year period. This will allow proper genetic counseling for carrier families. A total of 1450 individuals with different clinical histories were included in this study, they were referred for chromosome analysis to the cyto genetic laboratory, Medical Research Institute, University of Alexandria. Thorough clinical examination and pedigree analysis was done for all cases. Chromosome analysis was performed by GTG-banding and C-banding techniques for all cases. Thirty cases [2.07%] were found to have polymorphic inversion of 9 qh region, of which 25 and 5 included [p11q13], and [p12q13] inversion of chromosome 9 respectively. There were 16 females [53.33%] and 14 males [46.67%]. lnv[9] was found in 7 patients with Down syndrome, one with Cri du chat syndrome, two with dysmorphic features and developmental delay, and 3 with ambiguous genitalia. All cases had inherited the inversion from a carrier parent. In addition, inv[9] was found in 3 males with in fertility, 6 females with primary amenorrhea, and 8 couples with bad obstetric history [where one of the partner is a carrier]. Homozygous pericentric inversion of chromosome 9 was detected in one of the patients with primary amenorrhea. Finally, based on this clinical study, it can be concluded that inv[9] is not an uneventful rearrangement and that it leads to a relatively higher possibility of various clinical problems, such as reproductive failure and the occurrence of abnormalities in offspring. It is proposed that clinicians should not recognize inv[9] as a problem-free chromosomal rearrangement

Disease associated balanced chromosome rearrangements-report on 12 cases

The population frequency of familial disease balanced chromosome rearrangement with discordance for an abnormal phenotype is unknown. De novo balanced chromosome rearrangements are present in approximately 1:2000 newborn. The increased frequency of associated diseases may be due to truncation, inactivation or overexpression of specific genes. Uniparental disomy [UPD] has also been implicated. We report on 12 cases with apparently balanced chromosome rearrangements with abnormal phenotypes, 8 familial [5 families] and 4 de novo. Maternal inheritance accounted for 7/8 cases. The rearrangements included reciprocal translations in 8 cases, Robertsonian translocation in 2 cases and pericentric inversion in 2 cases. Apparently balanced rearrangements in general, represent an interpretational and counseling dilemma when detected in cases with abnormal phenotypes and/or mental retardation

Phenotypic variability in patients with isodicentric Y [p11.3]. Aclinical, cytogenetic and molecular study

Isodicentric [idic] chromosomes are the most common Y structural abnormalities and their influence on gonadal and somatic development is extremely variable. The prediction of their phenotypic consequences is often difficult because of the variety of genomic sequences concerned by duplications and deletions, and the variable degrees of mosaicism, 45, X cell line in particular, in various tissues. This study was conducted to provide more information on patients with idic [Yq] allowing a better phenotype-karyotype correlation and understanding the sexual differentiation in these patients. The study included 14 patients referred to the out patient clinic of the Human Genetics Department, Medical Research Institute, University of Alexandria. The reason for referral was genital ambiguity [8 patients], short stature with variable Turner stigmata [4 patients] and primary amenorrhea with normal height [2 patients]. All patients were subjected to clinical examination and chromosome analysis by GTG and CTG-banding techniques. Fluorescence in situ hybridization [FISH] and polymerase chain reaction [PCR] were done to determine the structure of the marker chromosomes detected by conventional methods. Chromosome analysis revealed a 45, X/46, X, idic [Y] [p11.3] in ten patients with variable degree of mosaicism, non mosaic 46, X, idic [Y] [p11.3] in two patients and a predominant 46, XX cell line along with 47, XX, idic [Y] [p11.3] cell line in two other patients .While the patients with an idic [Yq] described in this report were phenotypically different, all are considered as being at increased risk for gonadoblastoma. The great phenotypic variations seen in patients with an isodicentric Y chromosome greatly limit the genotype - phenotype correlation

Risk factors for hypospadias: a case control study

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this study we evaluated a spectrum of potential risk factors for hypospadias in which we focused on both paternal and maternal factors and chromosomal aberrations. Cases were selected from the Genetic Clinic, Medical Research Institute, University of Alexandria. A total of 176 cases with hypospadias were included in this study, and a matching control group ofnormal 300 boys for the association study. All cases were subjected to detailed family, pregnancy, genetic histories, clinical examination, and pedigree study. Chromosome analysis was performed using peripheral blood lymphocyte cultures by trypsin G-banding technique. Hormonal assays, abdominal and pelvic ultrasound were carried out according to case presentation. Both parents of cases and the control group completed written questionnaires. Abnormal karyotyes were detected in 23 cases [13.07%] associated with other anomalies, sex chromosome abnormalities were present in 69.56% and autosomal aberrations in 30.43%. Patients with chromosomal abnormalities were excluded from the association study. Logistic regression analysis was used to assess the independent contribution of different factors to the risk of hypospadias. Our data did not support an association with increased parental age. The most profound result was the increased risk of hypospadias for boys with positive family history [n=23; OR=26.36; 95%Cl: 5.90-164.23]. Strong indications for an increased risk of hypospadias were also found with low birth weight [n=45; OR=1 3.47; 95%Cl=6.09-30.70], preterm birth [n=6; OR=1 2.20; 95%Cl=1.45-271.47], twin or triplet pregnancy [n=4; OR=8.03; 95%Cl=0.84-190.23], and when mothers had preeclampsia [n=16; OR=11.56; 95%Cl=3.11-50.77]. Associations with pregnancy achieved with fertility treatment, and mother used iron supplements were also found. In conclusion, routine karyotype screening permits the diagnosis of chromosomal anomalies especially in those with the most severe forms of hypospadias and additional anomalies. Several risk factors have been identified for hypospadias which support the idea that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones before conception or during fetal development play a role in the etiology of hypospadias

C-band heteromorphism in breast cancer patients

C-band heteromorphism, including size localization variants, has been shown to correlate well with the occurrence of malignant diseases. This study was conducted to investigate the aberration of the C-band region of chromosomes 1, 9 and 16, including size variation, intra- pair size asymmetry and inversion by comparing the frequency of heteromorphism in patients with breast cancer and healthy subjects. This is useful to establish the significance of the variability of chromosome constitutive heterochromatin areas in a risk of malignancy. The study included 27 female patients with breast cancer and 30 normal healthy female subjects as controls. Peripheral lymphocytes culture and C-banding were done for all of them. The size of the heterochromatic region was evaluated using 16 p as a reference. Size heteromorphism between homologous chromosomes was considered when there was an intra-pair difference of one or more levels. Inversions, whether partial or total, were recorded. There was a significant increase in the size of C-band for chromosome 1 between patients and controls [X2 = 9.17]. Intra-pair size asymmetry of heterochromatin was more frequent in breast cancer patients than in the controls and the differences were statistically significant for chromosomes 1, 9 and 16. For localization variants, a significant increase in the frequency of partial inversion in chromosome No. 1 was found between the two groups [X2 = 4.44]

Detection of microdeletions involving the DAZ locus in idiopathic male infertility

Deletions of the AZFc [azoospermic factor c] region of the Y chromosome including DAZ gene are the most common known cause of spermatogenic failure. This study was conducted with the aim of detecting Y chromosome microdeletions involving the DAZ locus in idiopathic male infertility to allow rapid and accurate diagnosis required for proper genetic counseling. The study included 30 male patients with idiopathic azoospermia [24/30] or oligozoospermia [6/30]. A control group consisted of 10 normal fertile males and 5 females. All cases were subjected to detailed history, clinical examination, assessment of testicular volume, semen analysis, serum hormonal profile [FSH, LH, testosterone], testicular biopsy, chromosome analysis, polymerase chain reaction [PCR] amplification of two specific loci of the DAZ gene on the Y chromosome [sY254 and sY255], single strand conformations polymorphism analysis [SSCP]. The result of the study revealed that deletions involving the sY245 and sY255 DAZ loci were found in 4 cases [4/30; 13.3%]; 3 azoospermic patients and one with severe oligozoospermia. All four cases with microdeletions had decreased testicular volume, normal serum LH and T, serum FSH was elevated in 3 of them and normal in one. The two loci were amplified normally in the male control group and failed to amplify in the female control group. SSCP analysis failed to find any point mutations in sY254 and sY255 in patients with absence of microdeletions of DAZ gene. In conclusion, the estimated frequency of microdeletions involving the DAZ locus is 13.3% in azoospermic and severely oligozoospermic Egyptian men with idiopathic infertility. Polymerase chain reaction amplification of the DAZ locus is a rapid and accurate method for the diagnosis of microdeletions of the Y chromosome in patients with idiopathic infertility especially those seeking micromanipulation assisted reproduction