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PubMed2001

Genetic markers of male infertility: Y chromosome microdeletions and cystic fibrosis transmembrane conductance gene mutations.

Today, approximately 15% of couples have reduced fertility. In most cases the reason is male infertility, usually of genetic origin. Thus, in the context of research in genes involved in reproduction and sex determination, genetic defects in gametogenesis are being extensively studied. The most frequent pathogenic causes of male infertility are Y chromosomal microdeletions and obstructive azoospermia due to congenital absence of the vas deferens (CAVD) in the presence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We have investigated the most common CFTR gene alterations in Croatian men with CAVD, using Roche research prototype assays. Results revealed that the 5T variant was present in 27% of the subjects. The F508 deletion was found in 21% of the subjects. It was the most frequent mutation, although its incidence was much lower than among patients with cystic fibrosis. The prevalence of microdeletions in the azoospermia factor region (AZF) of the Y chromosome in Croatia was 4.5%. This is the first report of Y microdeletions in the Croatian population. Genetic counseling of all couples with the diagnosis of male infertility is recommended before intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection, and should also include AZF and CFTR genotyping. Couples requesting assisted reproductive treatment should be offered molecular analysis of the CFTR gene, if male infertility due to obstructive azoospermia is the underlying cause. Also, men with severe oligozoospermia or non-obstructive azoospermia seeking assisted reproductive treatment should be screened for deletions in the Y chromosome.

Chromosome Deletion↗
PubMed2002

Microdeletions in the Y chromosome of patients with idiopathic azoospermia.

AIM: To evaluate the occurrence and prevalence of microdeletions in the gamma chromosome of patients with azoospermia. METHODS: DNA from 29 men with idiopathic azoospermia was screened by polymerase chain reaction (PCR) analysis with a set of gamma chromosome specific sequence-tagged sites (STSs) to determine microdeletions in the gamma chromosome. RESULTS: Deletions in the DAZ (deleted in azoospermia) loci sgamma254 and sgamma255 were found in three patients with idiopathic azoospermia, resulting in an estimated frequency of deletions of 10.7% in idiopathic azoospermia men. CONCLUSION: We conclude that PCR analysis is useful for the diagnosis of microdeletions in the Y chromosome, which is important when deciding the suitability of a patient for assisted reproductive technology such as testicular sperm extracion-intracytoplasmic sperm injection (TESE-ICSI).

Adult↗
PubMedDate not supplied

[Role of Yq11-chromosome microdeletion in the development of nonobstructive infertility in men].

Recent studies have shown that a significant proportion of men with severe infertility had microdeletions of the Y-chromosome. It has thus become important to screen men with a high risk of the Y-chromosome microdeletions, as this will determine if counseling is needed prior to starting infertility treatment. The current state of knowledge about the nature of genes responsible for spermatogenesis and significance of microdeletions of the Y-chromosome for male infertility are analyzed in the review.

Chromosome Deletion↗
PubMed2002

PCR analysis of Yq microdeletions in infertile males, a study from South India.

AIM: To estimate the frequency of microdeletions in the long arm of Y-chromosome of 20 infertile males from South India. METHODS: Polymerase chain reaction (PCR) amplification using Y-specific STS of azoospermia factor (AZF) regions i.e., SY 84 for AZFa, SY 127 for AZFb and SY 254 for AZFc. RESULTS: Of the 20 infertile subjects 3 (15 %), one azoospermic and two oligozoospermic, showed microdeletions in the AZF region of Y-chromosome. CONCLUSION: The frequency of deletions involving AZF region of the Y-chromosome is 15 % in azoospermic and severely oligozoospermic infertile men. PCR amplification of AZF locus is useful for the diagnosis of microdeletions in the Y-chromosome.

Base Sequence↗
PubMed2004

[A cytogenetic and molecular genetic study on microdeletion of AZF region on Y chromosome].

OBJECTIVE: To study the morphology of Y chromosome and microdeletion of the correlated specific azoospermia factor(AZF) region on Y chromosome in cases of azoospermia and to identify the genetic diagnosis made for male infertility patients. METHODS: Peripheral blood samples were taken from two patients with azoospermia, and then were examined by use of G banding, C banding cytogenetic analysis and multiplex polymerase chain reaction (PCR) microdeletion analysis. RESULTS: The karyotypes of the two cases were 45, X, -Y, -22, +der(Y)t(Y;22)(q11.2;q11.2) and 46, XY, del(Y)(q11.2) respectively. In 12 sequence-tagged sites(STS) of AZFa, AZFb, AZFd, AZFc, only one was detected in the first case and two were detected in the other case. CONCLUSION: The cytogenetic analysis and the detection of AZF microdeletion on Y chromosome are essential to the final genetic diagnosis to be made for male infertility patients.

Chromosome Deletion↗
PubMed2004

Clinical and pathological correlation of the microdeletion of Y chromosome for the 30 patients with azoospermia and severe oligoasthenospermia.

AIM: To review the accumulated 30 patients with different area of Y chromosome microdeletions, focusing on their correlation with the clinical and pathological findings. METHODS: A total of 334 consecutive infertile men with azoospermia (218 patients) and severe oligoasthenospermia (116 patients) were screened. Complete physical and endocrinological examinations, general chromosome study and multiplex polymerase chain reaction assay to evaluate the Y chromosome microdeletion were performed. Ten patients received testicular biopsy. Then the clinical and pathological findings were analyzed with reference to the areas of Y chromosome microdeletion. RESULTS: There is a decline of the percentage of sperm appearing in semen in the group that the gene deletion region from AZFc to AZFb. The clinical evidence of the impairment (decreased testicular size and elevated serum FSH) is also relevantly aggravated in this group. However, the pathology of testicular biopsy specimen was poorly correlated with the different deletion areas of the Y chromosome, which may be due to the limited number of specimens. CONCLUSION: The clinical correlation of spermatogenic impairment to the different AZF deletion regions may provide the information for the infertile couples in pre-treatment counseling.

Adult↗
PubMed2005

[A genetic study on microdeletion of azoospermia factor region on Y chromosome of azoospermia and oligozoospermia patients].

OBJECTIVE: To investigate the genetic causes of azoospermia and severe oligozoospermia. METHODS: Cytogenetic analysis and multiplex polymerase chain reaction(PCR) analysis were done on the 148 patients with azoospermia and serious oligozoospermia. RESULTS: Eleven of the 148(7.4%) cases showed microdeletion of at least one STS. In fifteen STS of AZFa, AZFb,AZFd, AZFc, thirteen STS, eleven STS,two STS and one STS microdeletion were found in each case respectively, including two with 12 STS, five with 5 STS microdeletion.Seven cases had chromosomal morphologic changes(4.7%),four had deletion and one had deletion with translocation of long arm on Y chromosome. One had enlarged region one band two(q12) on long arm of Y chromosome and one had reciprocal translocation of autosomes. CONCLUSION: The findings indicated that AZF microdeletion and chromosomal abnormality should be important causes of male infertility.

Azoospermia↗
PubMed2006

[Detection and related analysis to chromosome 22q11 microdeletion in patients with congenital heart diseases].

OBJECTIVE: To ascertain 5 short tandem repeat (STR) markers as qualified tools for detecting chromosome 22q11 deletion and to understand the prevalence and clinical importance of the deletions in patients with congenital heart diseases (CHD) from Chinese Han population. METHODS: The authors selected 5 new tetranucleotide repeat markers, 22D_4_1, 22D_4_2, 22D_4_3, 22D_4_4 and D22S873 located in the proximal region of chromosome 22q11 deletion. One hundred and sixty-three unselected CHD patients and their unaffected parents were analyzed by genotyping of these new tetranucleotide STR markers to detect 22q11 deletion. With fluorescence in situ hybridization (FISH, LSI dual color DNA probe), the deletion status was confirmed in all patients with deletions and some patients without deletions. RESULTS: The heterozygosity of these STR markers in normal population was more than 0.7, except for 22D_4_1 and 22D_4_2 that were 0.65 and 0.52 respectively. Twelve cases of 163 CHD patients (7.36%) had the deletions at chromosome 22q11. The deletions were confirmed in 9 of 12 patients by FISH, except for 2 cases who had unique nested deletion and 1 case who had nested distal deletion. One hundred and ten patients were associated with ventricular septal defect (VSD); and 9 (8.18%) of these cases had microdeletion. Twenty-one patients were associated with tetralogy of Fallot (TOF); and 3 (14.3%) of these cases had microdeletion. CONCLUSION: This study demonstrated that genotyping of 5 STR markers was a useful mean of detecting 22q11 microdeletion in clinical diagnosis owing to its rapid experimental procedure, cost effectiveness and high resolution. 22q11 deletion was common in CHD patients, particularly in VSD and TOF patients, from Chinese Han population.

Chromosome Deletion↗
PubMed1996

Pitt-Rogers-Danks syndrome: the result of a 4p microdeletion.

Pitt-Rogers-Danks syndrome (PRDS) is a rare, presumed autosomal recessive, syndrome with pre- and postnatal growth retardation, microcephaly, characteristic facial appearance, seizures, unusual palmar creases and developmental delay. Since the first description in 1984, only 7 cases have been reported. We report the identification of a 4p microdeletion in 2 new patients, who were previously diagnosed with PRDS, as well as the sibs in Pitt et al. [1984]. PRDS can no longer be considered autosomal recessive. Although our cases are attributable to a microdeletion in 4p16, it is uncertain if the critical region involves a single locus or multiple loci or to what extent this region overlaps with the critical region for Wolf-Hirschhorn syndrome.

Abnormalities, Multiple↗
PubMed2001

Craniofacial anthropometric analysis in patients with 22q11 microdeletion.

Microdeletions in the 22q11 region are associated with a wide range of overlapping phenotypes. The main manifestations of the syndrome include palatal anomalies such as cleft palate or velopharyngeal insufficiency, conotruncal heart defects, hypocalcemia, immune disorders, and minor facial anomalies. Because of the wide variability, facial changes appear to be the most constant manifestation of the syndrome and characteristic for informed physicians. The purpose of this study is to report the preliminary results of a detailed analysis of anthropometric data (35 measurements) in 15 patients (7 females and 8 males between 5 and 38 years of age, all white Europeans) with a 22q11 microdeletion. Objective anthropometric study showed that 19 measurements and 7 indexes were significantly different between 22q11 patients and normative database. The typical face showed a short forehead with an anterior vertical excess. Downslanting eyes and large binocular width were the most common anomalies in the orbital area. The nose showed anomalies with a large root, a short tip, and a narrow alar base. There was a narrowing of the mouth and thin lips. Ears were small and slightly disharmonic for the children. Statistical comparison between children (10 cases) and adults (5 cases) showed that craniofacial assessment was more demonstrative in children than in adults.

Adolescent↗
PubMed2001

Refined FISH characterization of a de novo 1p22-p36.2 paracentric inversion and associated 1p21-22 deletion in a patient with signs of 1p36 microdeletion syndrome.

We report on a 10-year-old boy presenting with obesity, moderate mental retardation, large anterior fontanelle at birth, mild physical anomalies including mid-face hypoplasia, deep-set eyes, long philtrum, and small mouth. He was found to carry a paracentric inversion inv(1)(p22p36.2) associated with a 10 cM deletion at the proximal breakpoint. By YAC FISH, the boundaries of the deletion were established at IB1028 (1p21) and WI-5166 (1p22) STSs contained in YACs 781E8 and 954F6, respectively. This large region, covering about 10 cM, contains the COL11A1 and AMY2B genes, whose haploinsufficiency does not seem to contribute significantly to the clinical phenotype. On the other hand, the patient's clinical manifestations, also including visual problems and moderate mental retardation, are those typically observed in the 1p36 deletion syndrome. Refined mapping of the telomeric 1p36.2 inversion breakpoint was obtained by FISH of a PAC contig constructed to encompass this subinterval of the 1p36 microdeletion syndrome region. PACs 1024B10 and 884E7 were found to span the breakpoint, suggesting that the clinical signs of the 1p36 microdeletion syndrome might be due to disruption of a sequence lying at 1p36.2.

Abnormalities, Multiple↗
PubMed2004

De novo complex chromosomal rearrangements (CCR) involving chromosome 1, 5, and 6 resulting in microdeletion for 6q14 in a female carrier with psychotic disorder.

A 23-year-old obese woman with a psychotic disorder was found to have a de novo apparently balanced complex chromosomal rearrangement involving chromosomes 1, 5, and 6. Molecular cytogenetic analyses using high-resolution comparative genomic hybridization (HR-CGH) showed a microdeletion at 6q14 in a der(6). Application of HR-CGH facilitated detection of micro-rearrangement of all de novo apparently balanced complex chromosomal rearrangements (CCR) and supported the localization of the breakpoint. According to our knowledge, no constitutional interstitial microdeletion of chromosome 6q14 has been found associated with a schizoid-type phenotype.

Adult↗
PubMed2006

Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization.

In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

Abnormalities, Multiple↗
PubMed2007

Novel microdeletion in the transforming growth factor beta type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma.

Mutations in the tumor suppressor gene transforming growth factor beta (TGFB) Type II receptor (TGFBR2) are frequently found in many cancers with microsatellite instability, but are less common in lung cancer. In the present study, we looked for mutations in TGFBR2 in nonsmall cell lung carcinoma (NSCLC) cells and tissues. A novel homozygous microdeletion (c.492_507del) was identified in two cell lines derived from the same giant cell carcinoma (GCC) and was confirmed in the corresponding tumor tissues. Furthermore, a heterozygous c.492_507del was found in the germ-line of one patient, as well as in the other GCC cases and some large cell carcinomas (LCC) but not in other subtypes of NSCLC. The 16 bp-microdeletion introduced a premature stop codon at positions 590-592 of the cDNA, resulting in a truncated TGFBR2 protein with a mutated transmembrane domain and loss of kinase domain. The GCC cells were characterized as being unresponsive to TGFB induction both in growth inhibition and stimulation of extracellular matrix protein. Moreover, after the reconstitution of wild-type TGFBR2 expression, the sensitivity to TGFB was restored. Therefore, mutated TGFBR2 seems to play an important role in the abrogation of TGFB signal transduction in GCC cells.

Adult↗
PubMed1996

Familial non-syndromic conotruncal defects are not associated with a 22q11 microdeletion.

Molecular studies have shown microdeletions in region q11 of chromosome 22 in nearly all patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes (DGS, VCFS and CTAFS, respectively) and in a high percentage of non-syndromic familial cases of conotruncal defects (CTD). CTD account for roughly a fourth to a third of all non-syndromic congenital heart defects (CHD), thus, 22q11 could harbor a major genetic factor of CHD. We searched for a 22q11 microdeletion in familial cases of non-syndromic CTD. Thirty-six cases of various isolated CTD, that is without history of hypocalcemia, immune deficiency, absent thymus, and dysmorphic appearance, were selected. With 48F8, a cosmid probe localized in the smallest deleted region of the DiGeorge critical region (DGCR), we found no deletions by fluorescence in situ hybridization in these 36 affected individuals of 16 families with recurrent CTD. Moreover, D22S264, a microsatellite localized at the distal part of the largest deleted region, was used to genotype the patients. Thirty-two patients out of 37 were heterozygous and hence not deleted at this locus, whereas 5 were uninformative. In conclusion, there are no large deletions in familial cases of various CTD, whether these defects are identical or not within a family. This result does not rule out other minor anomalies in this chromosomal region.

Adolescent↗
PubMed1998

Clinical characteristics of children with hypoparathyroidism due to 22q11.2 microdeletion.

UNLABELLED: The phenotypes of chromosomal 22q11.2 microdeletion are quite variable among individuals and hypoparathyroidism (HP) constitutes a definite portion of the clinical spectrum. For the correct diagnosis and pertinent follow up of the HP children due to del22q11.2, we tried to delineate the clinical characteristics of such patients. By employing fluorescence in situ hybridization (FISH) to all the patients diagnosed as HP in our clinic, ten possessed the 22q11.2 microdeletion. Among them, the incidence of cardiac defect (5/10), recurrent infection (1/10) and cleft palate (1/10) was modest. Additionally, seven of them had been diagnosed as HP during the infantile period, when their facial abnormality and intellectual problem had not become evident. Notably, two patients were complicated by Graves disease, while the association of idiopathic thrombocytopenic purpura was also observed in two girls. CONCLUSION: HP due to del22q11.2 may be misdiagnosed as idiopathic, especially in an infant who lacks apparent complications like cardiac anomaly. They should be closely followed up for auto-immune complications.

Child↗
PubMed2004

Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions.

NF1 microdeletion syndrome is caused by haploinsufficiency of the NF1 gene and of gene(s) located in adjacent flanking regions. Most of the NF1 deletions originate by non-allelic homologous recombination between repeated sequences (REP-P and -M) mapped to 17q11.2, while the remaining deletions show unusual breakpoints. We performed high-resolution FISH analysis of 18 NF1 microdeleted patients with the aims of mapping non-recurrent deletion breakpoints and verifying the presence of additional recombination-prone architectural motifs. This approach allowed us to obtain the sequence of the first junction fragment of an atypical deletion. By conventional FISH, we identified 16 patients with REP-mediated common deletions, and two patients carrying atypical deletions of 1.3 Mb and 3 Mb. Following fibre-FISH, we identified breakpoint regions of 100 kb, which led to the generation of several locus-specific probes restricting the atypical deletion endpoint intervals to a few kilobases. Sequence analysis provided evidence of small blocks of REPs, clustered around the 1.3-Mb deletion breakpoints, probably involved in intrachromatid non-allelic homologous recombination (NAHR), while isolation and sequencing of the 3-Mb deletion junction fragment indicated that a non-homologous end joining (NHEJ) mechanism is implicated.

Base Sequence↗
PubMed2005

De novo t(7;10)(q33;q23) translocation and closely juxtaposed microdeletion in a patient with macrocephaly and developmental delay.

We have applied FISH with fully integrated BACs and BAC subfragments assessed in the human genome sequence to a de novo t(7;10)(q33;q23) translocation in a patient with developmental delay and macrocephaly. The translocation breakpoints disrupt the SEC8L1 gene on chromosome 7 and the PTEN gene on chromosome 10. RT-PCR demonstrated chimeric transcripts containing the first 11 exons of SEC8L1 fused to exon 3 of PTEN. In addition to the balanced translocation, we found a 7-Mb deletion in the translocated part of chromosome 7 at 4-Mb distance of the translocation breakpoint. This microdeletion, which disrupts the PTN and TPK1 genes and deletes 29 bonafide genes and the T-cell receptor beta locus, arose in the paternal germline. The patient's phenotype may be caused by a dominant-negative effect of the SEC8L1-PTEN fusion protein and/or haploinsufficiency of the disrupted or deleted genes. Our study demonstrates that de novo translocations can be associated with microdeletions outside the breakpoint region(s), rendering the study and risk estimation of such breakpoints more complicated than previously assumed.

Abnormalities, Multiple↗