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PubMed2002

[The prognostic value of the site and extent of Y chromosome microdeletions on spermatogenesis].

Genes on Y-chromosome are involved in the regulation of spermatogenesis. Y-chromosome microdeletions were identified among infertile patients in a frequency of 7.5-15% on the long arm of the chromosome. These microdeletions were clustered in 3 main regions named AZFa, AZFb, and AZFc. Reanalyzing the histological findings in men with well-defined varying extent of Y-chromosome microdeletions improved our understanding of the prospect of finding testicular spermatozoa. The chances of finding spermatozoa were almost nil in men with microdeletions that include the complete AZFa region or AZFb region or at least two AZF regions. Large microdeletions that include the Yq tip were suggested to cause chromosomal instability and were shown to be prone to Y chromosome loss. In addition, a decrease of sperm count over time in men with AZFc deletions has been reported and the option of spermatozoa cryo-preservation need to be taken in consideration. Analysis of the Y-chromosome microdeletion was found to be of prognostic value in cases of infertility both in terms of clinical management as well as for understanding the etiology of the spermatogenesis impairment.

Chromosome Mapping↗
PubMed2003

[Establishment and preliminary application of screening methods for Y chromosome microdeletions in male infertility patients].

OBJECTIVE: To develop a multiplex PCR protocol, which could be suitable for routine screening of microdeletions on the Y chromosome in azoospermic and oligozoospermic male infertility patients. METHODS: Five multiplex sets were established. Eighty-seven azoospermic and oligozoospermic patients undergoing intracytoplasmic sperm injection (ICSI) in the in vitro fertilization (IVF) center and 30 azoospermic men undergoing testicular biopsy in the clinic of Urology Surgery were screened for microdeletions of Y chromosome. RESULTS: A total of 19 (16.2%) cases of microdeletions were found in 117 azoospermic and oligozoospermic patients by screening of Y chromosome microdeletions. Of these, 11 cases (18.0%) were found in 61 oligozoospermic patients, and 8 cases (14.3%) were found in 56 azoospermic patients. CONCLUSION: The multiplex PCR protocol presented in this study is an easy-to-do and reliable method for detecting microdeletions on the Y chromosome. Routine screening of microdeletions on the Y chromosome for azoospermic and oligozoospermic patients is essential.

Chromosome Deletion↗
PubMed2004

Screening of Y chromosome microdeletion which contains AZF regions in 71 Turkish azoospermic men.

Screening of Y chromosome microdeletion which contains AZF regions in 71 turkish azoospermic men: In 71 Turkish men Y chromosome microdeletions have been studied before intracytoplasmic sperm injection (ICSI). DNA samples were amplified with 18 STS primers of the azoospermia factor (AZF) region on the Y chromosome by using multiplex polymerase chain reaction (PCR). Microdeletions were detected in 4 azoospermic men (5.6 %); one with a deletion in the AZFb region, while the 3 others had a large deletion extending over multiple chromosomal regions (AZFb+c+d and AZFa+b+c+d). In the patients with microdeletion, no spermatogenetic activity could be detected in testis biopsies. This result confirms the idea that Y chromosome microdeletion analysis is important in investigating the possibility of finding sperm in testicular sperm extraction (TESE). Therefore, we point out the importance of genetic testing and counselling regarding Y chromosome microdeletion for couples requesting ICSI.

Case-Control Studies↗
PubMed2004

[Chromosome microdeletions detected in mental retardation].

OBJECTIVE: To explore whether chromosomal microdeletions have a role in the pathogenesis of unexplained mental retardation (MR) and the value of fluorescence in situ hybridization (FISH) in the detection of microdeletions in MR. METHODS: Selection of patients was based on the following criteria: (1) MR with two or more of the following: dysmorphic features, prenatal growth retardation, postnatal growth abnormalities, a suggestive family history; (2) Chromosome karyotype at the level >450 bands was normal; (3) Exclusion of other identified genetic or environmental diagnosis. FISH was carried out with specific DNA probe to 47 undiagnosed MR to identify interstitial microdeletions and further screen the integrity chromosome subtelomere. RESULTS: Six cases were analyzed by FISH for special interstitial microdeletions and anomaly was found in one case with 7q11.23 deletion. Subtelomeric FISH analyses were performed in 46 patients, and two cases with a deletion of subtelomeric region of chromosome 6q and 2q respectively were identified. CONCLUSION: Chromosome microdeletions are supposed to be a significant cause of idiopathic MR, once recognizable syndromes have been excluded, FISH analyses for interstitial microdeletions and subtelomeric rearrangements are warranted in children with unexplained MR.

Chromosome Deletion↗
PubMed2005

[Study on the relationship between 22q11 microdeletion and congenital heart disease].

To investigate if microdeletion of chromosome 22q11 is an epidemiologically important cause of congenital heart disease (CHD), we studied 25 cases with CHD phenotypes. Venous blood samples were tested by fluorescence in situ hybridization (FISH) for microdeletion of 22q11. Among 23 cases with simple CHD, 19 were shown not to have microdeletion of 22q11 and the other 4 cases were shown to have 22q11 microdeletion. Microdeletion of 22q11 was found in 2 cases with Tetralogy of Fallot (TOF) accompanied by multiple malformations. The results suggested that microdeletion of 22q11 was associated with CHD.

Adolescent↗
PubMed2006

[Azoospermia factor microdeletions in idiopathic azoospermia and severe oligozoospermia].

OBJECTIVE: To observe the relationship between microdeletions of AZF( azoospermia factor) on Y chromosome in male with idiopathic azoospermia and severe oligozoospermia. METHODS: Only patients with an apparently normal 46,XY karyotype and normal FSH, LH and T were included in this study. Multiplex PCR was used to detect the sequence-tagged sites( STS) as follows :sY84, sY86, sY127, sY134, sY152, sY153, sY254, sY255, and ZFX/Y was used as internal control gene. RESULTS: No microdeletion was detected in the control whereas 8 microdeletion cases existed in 67 idiopathic azoospermia and severe oligozoospermia, including 4 in AZFc, 2 in AZFa + AZFc, 1 in AZFc + AZFb, and 1 in AZFb. The prevalence rate of microdeletion was 11.94%, which was statistically different from the control. CONCLUSION: Microdeletions in the AZF regions on the long arm of the Y-chromosome are associated with idiopathic azoospermic and severely oligozoospermic men. Multiplex PCR was a rapid and reliable method for screening microdeletions of AZF.

Adult↗
PubMed1999

Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection.

Cytogenetic and molecular deletion analyses of azoospermic and oligozoospermic males have suggested the existence of AZoospermia Factor(s) (AZF) residing in deletion intervals 5 and 6 of the human Y-chromosome and coinciding with three functional regions associated with spermatogenic failure. Nonpolymorphic microdeletions in AZF are associated with a broad spectrum of testicular phenotypes. Unfortunately, Sequence Tagged Sites (STSs) employed in screening protocols range broadly in number and mapsite and may be polymorphic. To thoroughly analyze the AZF region(s) and any correlations that may be drawn between genotype and phenotype, we describe the design of nine multiplex PCR reactions derived from analysis of 136 loci. Each multiplex contains 4-8 STS primer pairs, amplifying a total of 48 Y-linked STSs. Each multiplex consists of one positive control: either SMCX or MIC2. We screened four populations of males with these STSs. Population I consisted of 278 patients diagnosed as having significant male factor infertility: either azoospermia, severe oligozoospermia associated with hypogonadism and spermatogenic arrest or normal sperm counts associated with abnormal sperm morphology. Population II consisted of 200 unselected infertile patients. Population III consisted of 36 patients who had previously been shown to have aneuploidy, cytological deletions or translocations involving the Y-chromosome or normal karyotypes associated with severe phenotype abnormalities. Population IV consisted of 920 fertile (control) males. The deletion rates in populations I, II and III were 20.5%, 7% and 58.3%, respectively. A total of 92 patients with deletions were detected. The deletion rate in population IV was 0.87% involving 8 fertile individuals and 4 STSs which were avoided in multiplex panel construction. The ability of the nine multiplexes to detect pathology associated microdeletions is equal to or greater than screening protocols used in other studies. Furthermore, the data suggest a fourth AZF region between AZFb and AZFc, which we have termed AZFd. Patients with microdeletions restricted to AZFd may present with mild oligozoospermia or even normal sperm counts associated with abnormal sperm morphology. Though a definitive genotype/phenotype correlation does not exist, large deletions spanning multiple AZF regions or microdeletions restricted to AZFa usually result in patients with Sertoli Cell Only (SCO) or severe oligozoospermia, whereas microdeletions restricted to AZFb or AZFc can result in patients with phenotypes which range from SCO to moderate oligozoospermia. The panel of nine multiplexed reactions, the Y-deletion Detection System (YDDS), provides a fast, efficient and accurate method of assessing the integrity of the Y-chromosome. To date, this study provides the most extensive screening of a proven fertile male population in tandem with 514 infertile males, derived from three different patient selection protocols.

Female↗
PubMed2005

Novel rearrangement of chromosome band 22q11.2 causing 22q11 microdeletion syndrome-like phenotype and rhabdoid tumor of the kidney.

The 22q11.2 microdeletion syndrome is the most frequent microdeletion syndrome in humans, yet its genetic basis is complex and is still not fully understood. Most patients harbor a 3-Mb deletion (typically deleted region [TDR]), but occasionally patients with atypical deletions, some of which do not overlap with each other and/or the TDR, have been described. Microduplication of the TDR leads to a phenotype similar, albeit not identical, to the deletion of this region. Here we present a child initially suspected of having 22q11 microdeletion syndrome, who in addition developed a fatal malignant rhabdoid tumor of the kidney. Detailed cytogenetic and molecular analyses revealed a complex de novo rearrangement of band q11 of the paternally derived chromosome 22. This aberration exhibited two novel features. First, a microduplication of the 22q11 TDR was associated with an atypical 22q11 microdeletion immediately telomeric of the duplicated region. Second, this deletion was considerably larger than previously reported atypical 22q11 deletions, spanning 2.8 Mb and extending beyond the SMARCB1/SNF5/INI1 tumor suppressor gene, whose second allele harbored a somatic frameshift-causing sequence alteration in the patient's tumor. Two nonallelic homologous recombination events between low-copy repeats (LCRs) could explain the emergence of this novel and complex mutation associated with the phenotype of 22q11 microdeletion syndrome.

Chromosome Deletion↗
PubMed2006

Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.

Child↗
PubMed2000

Y chromosome microdeletion screening in infertile men.

Molecular analysis of Y-chromosomal microdeletions is routinely performed in the work-up of male infertility, in order to establish a diagnosis and for genetic counseling of the couple, since such microdeletions are transmitted to the male offspring. The review of published data shows that microdeletions are relatively common in patients with azoospermia or severe oligozoospermia, with wide variations in the reported deletion frequency depending mainly on the selection criteria. In general, patients with proximal deletions, involving the AZFa and/or the AZFb region show severe defects of spermatogenesis with a high prevalence of Sertoli cell only syndrome, while deletions of the distal AZFb and of the AZFc region can be compatible with residual spermatogenesis. Microdeletions have been only sporadically found in normozoospermic patients. For the time being the molecular analysis of microdeletions of the Y chromosome is indicated in infertile patients with sperm concentration <5 x 10(6)/ml and in men undergoing assisted reproduction techniques, since the genetic defect and, most probably, the related infertility problem will be transmitted to the sons.

Gene Deletion↗
PubMed1999

Chromosome 22q11 microdeletion and congenital heart disease--a survey in a paediatric population.

UNLABELLED: Congenital heart disease is a common finding in patients with microdeletion of chromosome 22q11. To determine if the deletion is an epidemiologically important cause of congenital heart disease, we studied a consecutive series of children attending a paediatric cardiac clinic and of neonates diagnosed as having structural congenital heart disease. Venous blood samples were tested by fluorescent in-situ hybridisation analysis for microdeletion of chromosome 22q11 using probe D22S75. Each patient was examined for the other clinical features associated with microdeletion of chromosome 22q11, and any family history of congenital heart disease recorded. Of 151 families approached, 111 participated and a fluorescent in-situ hybridisation result achieved in 87. One patient with microdeletion of chromosome 22q11 was identified; the clinical features were those of DiGeorge syndrome. Two patients with CHARGE association, two with nasal speech, ten with high arched palate, and 15 with minor facial dysmorphic features had no deletion. CONCLUSION: Microdeletion of chromosome 22q11 detected by probe D22S75 is rare in this consecutive series of patients with structural congenital heart disease.

Child↗
PubMed2005

Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes.

Holoprosencephaly (HPE), the most common structural malformation of the forebrain in humans, can be detected early during pregnancy using prenatal ultrasonography . Among foetuses with a normal karyotype, 14% have mutations in the four main HPE genes (SHH, ZIC2, SIX3 and TGIF). Genomic rearrangements have now been implicated in many genetic diseases, so we hypothesized that microdeletions in the major HPE genes may also be common in HPE foetuses with severe phenotype or other associated malformations. We screened the DNA obtained from 94 HPE foetuses with a normal karyotype for the presence of microdeletions involving the four major HPE genes (SHH, ZIC2, SIX3 and TGIF). Thirteen of the foetuses had a point mutation in one of the 4 genes and 81 had no known mutations. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis was used for rapid determination of HPE genes copy numbers and the identified microdeletions were confirmed by real time quantitative PCR, or fluorescent in situ hybridization (FISH) (if a cell line was available). Microdeletions were detected in 8 of 94 foetuses (8.5%) (2 in SHH, 2 in SIX3, 3 in ZIC2 and 1 in TGIF genes), and only among the 81 foetuses with a normal karyotype and no point mutations. These data suggest that microdeletions in the four main HPE genes are a common cause of prenatal HPE, as well as point mutations, and increase the total diagnosis rate close to approximately 22.3% of foetuses with normal karyotype. Detection can be achieved by the QMPSF testing method that proved to be efficient for testing several genes in a single assay.

Chromosome Deletion↗
PubMed1996

Mosaicism of a microdeletion of 486 bp involving the CGG repeat of the FMR1 gene due to misalignment of GTT tandem repeats at chi-like elements flanking both breakpoints and a full mutation.

Although the majority of fragile-X patients demonstrate methylation and a much-expanded CGG repeat region in the 5'-untranslated region of exon 1 of the FMR1 gene, exceptional cases have been reported to be due to deletions. However, fine mapping of the deletion breakpoints is still lacking and so far the underlying mechanism is unknown. We identified a fragile-X patient mosaic for a full mutation and a microdeletion. The microdeletion spans 486 bp, involving 168 bp upstream from the CGG repeat region, the entire CGG repeat region, exon 1, and 138 bp of the first intron of the FMR1 gene. In contrast to previous reports, the 5' breakpoint does not fall into the hotspot region. The proximal breakpoint, 5'-GTGGTT/T-3', and the distal breakpoint, 5'-GTTGTT/GG-3', can be characterized as chi-like elements and are flanked by direct tandem repeats. Mosaicism of a full mutation and the microdeletion in the DNA of the patient's leukocytes indicates the mitotic origin of the microdeletion. Since the microdeletion allele is unmethylated, it can be concluded that it is not derived from the methylated full mutation but from an unmethylated premutational allele.

Base Composition↗
PubMed2001

Analysis for microdeletions of Y chromosome in a single spermatozoon from a man with severe oligozoospermia.

Since the association between Y chromosome deletions and spermatogenic failure was demonstrated in 1976, there have been many reports of Y chromosome microdeletions. Peripheral blood lymphocytes (PBLs) have been used for the analysis because the method is convenient, materials are easy to obtain, and PBL genomic DNA is similar to that of germ cells such as spermatozoa. However, PBLs originate from somatic tissue, not from germ cells. In this study, we analyzed 30 spermatozoa in semen ejaculated by an infertile male with Y chromosome microdeletions, while 50 spermatozoa from a normal fertile male were used as a control. The same Y chromosome microdeletion as that found in PBL was identified in each of the 12 spermatozoa which contained the Y chromosome in the infertile patient. These results indicated that spermatozoa (germ cells) had the same Y chromosome microdeletion as PBL (somatic cells). This supports the conjecture that microdeletions are transmitted to the next generation via the treatment of infertility by intracytoplasmic sperm injection.

Base Sequence↗
PubMed2001

Y-chromosome microdeletion and phenotype in cytogenetically normal men with idiopathic azoospermia.

OBJECTIVE: To determine the prevalence of microdeletions of the long arm of chromosome Y within the AZFa, AZFb, and AZFc subregions in patients with idiopathic azoospermia, and then correlate the microdeletions with clinical phenotypes to determine the most important subregion for screening. DESIGN: Controlled clinical study. SETTING: Male infertility clinic, Kobe University Hospital. PATIENT(S): Among 89 consecutive azoospermic patients, those whose infertility was related to known hereditary, endocrine, or obstructive causes or a cytogenetic abnormality were excluded; 54 remaining patients were studied using a polymerase chain reaction (PCR). Of these patients, 33 had Sertoli cell only syndrome, 10 had maturation arrest, and 11 had hypospermatogenesis. INTERVENTION(S): Blood and semen samples and testicular biopsies were obtained from all of the participants. MAIN OUTCOME MEASURE(S): We performed semen analysis, polymerase chain amplification of 28 DNA loci on the long arm of the Y chromosome involving the DAZ (deleted in azoospermia), and measured the plasma FSH, LH, testosterone, prolactin, and estradiol levels. RESULT(S): Microdeletions were detected in 14 of the 54 patients (nine with Sertoli cell only, three with maturation arrest, and two with hypospermatogenesis). Most microdeletions involved AZFb or AZFc. Patients with hypospermatogenesis or maturation arrest showed deletion only in AZFc. The DAZ gene was deleted in four patients with Sertoli cell only and one patient with maturation arrest. The RBM gene was deleted in two patients with Sertoli cell only who had particularly large deletions, but in no patients with arrest or hypospermatogenesis. CONCLUSION(S): Cytogenetically azoospermic patients should be examined for microdeletions before undertaking assisted reproduction. AZFc may be the most important subregion to screen. In addition, intact AZFa and AZFb subregions may be important for the presence of germ cells.

Adult↗
PubMed2001

Ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions in a 17-year-old man.

OBJECTIVE: To describe clinical and laboratory features of a patient with 45,X/46,XY mosaic karyotype and Y chromosome microdeletions and to discuss the diagnostic problems in his management. DESIGN: Case report. SETTING: University department. PATIENT(S): A 17-year-old man with ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions. INTERVENTION(S): Testicular ultrasonography, karyotype, open testicular biopsy, polymerase chain reaction (PCR) screening for cystic fibrosis, PCR screening for Y chromosome microdeletions in peripheral blood and testicular tissue, and reverse transcriptase PCR in testicular tissue for Y chromosome microdeletions. MAIN OUTCOME MEASURE(S): Avoidance of dissemination of testicular cancer. RESULT(S): The patient was referred for bilateral orchiectomy. CONCLUSION(S): 45,X/46,XY mosaic karyotype is associated with a broad spectrum of phenotypes that includes female with Turner syndrome, male with mixed gonadal dysgenesis, male pseudohermaphroditism, and apparently normal male. Microdeletions of the long arm of the Y chromosome may be associated with Y chromosomal instability, leading to formation of 45,X cell lines. 45,X/46,XY males carry an increased risk for gonadal tumors and must be followed closely.

Adolescent↗
PubMed2003

Cytogenetic and Y chromosome microdeletion screening of a random group of infertile males.

OBJECTIVE: To assess whether to perform routine cytogenetic and Y chromosome microdeletion screening on all infertile male patients. DESIGN: A cytogenetic and Y microdeletion study of a random group of infertile men. SETTING: University department. PATIENT(S): In total, 40 patients had azoospermia (21 nonidiopathic), 27 had severe oligozoospermia/oligoasthenozoospermia (<or=5 x 10(6)/mL) (5 nonidiopathic), 20 had oligozoospermia/oligoasthenozoospermia (5-20 x 10(6)/mL) (6 nonidiopathic), and 16 had asthenozoospermia (5 nonidiopathic). Many were candidates for intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Collection of blood samples from all patients and buccal cells from one patient. MAIN OUTCOME MEASURE(S): Karyotype analysis, polymerase chain reaction (PCR) screening for Y chromosome microdeletions, and fluorescence in situ hybridization of abnormal chromosomes. RESULT(S): Ten (9.7%) subjects, including one nonidiopathic patient, were found to have an abnormal karyotype. Two idiopathic azoospermic patients were missing large portions of Y chromosome euchromatin, confirmed by PCR analysis and an additional idiopathic azoospermic patient had a Y chromosome microdeletion. CONCLUSION(S): Routine cytogenetic analysis of all infertile male patients is required but it may be advisable to limit routine Y chromosome microdeletion screening to patients with severe male factor infertility (<or=5 x 10(6)/mL).

Chromosome Deletion↗
PubMed2003

Y chromosome microdeletions in infertile men with cryptorchidism.

OBJECTIVE: To determine whether cryptorchidism associated with azoospermia or oligozoospermia may be due to microdeletions of the Y chromosome. DESIGN: Controlled clinical study. SETTINGS: Division of Medical Genetics and the Andrology Centre, Department of Obstetrics and Gynecology, University Medical Center, Ljubljana. PATIENT(S): Ninety men from infertile couples (36 azoospermics, 35 oligozoospermics, and 19 normozoospermics) with a medical history of cryptorchidism. Nineteen excryptorchid patients with cryptorchidism and Y chromosome microdeletions among 3099 patients from 14 publications. INTERVENTION(S): Collection of semen and blood samples. MAIN OUTCOME MEASURE(S): Medical history, testicular volume, sperm characteristics, serum FSH levels, testicular histology, presence or absence of Y chromosome microdeletions, including all known Y chromosome genes/gene families in the azoospermia factor (AZF) region. RESULT(S): Deletions of the Y chromosome were found in 2 out of 71 cryptorchid patients with azoospermia or oligozoospermia (2.8%). The literature review showed that the incidence of microdeletions in infertile patients with cryptorchidism is lower in comparison with the general population of infertile men (4.9% vs. 8.1%), and that the frequency of cryptorchidism in patients with Y chromosome deletions (6 out of 103, 5.8%) is significantly lower in comparison to infertile patients without deletions (178 out of 1141, 15.6%). CONCLUSION(S): No causal relation exists between Y chromosome microdeletions and cryptorchidism.

Adult↗