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PubMed2002

[Microdeletion 22q11.2. A too rarely diagnosed genetic change in psychiatric illnesses].

Microdeletion 22q11.2 with an estimated incidence of 1:4000 is known to cause the DiGeorge syndrome (DGS) or the velocardiofacial syndrome (VCFS), both usually being diagnosed in the newborn period or childhood. Recent studies have shown that children suffering from VCFS frequently develop psychiatric disorders in late adolescence or adulthood. Here we report the case of a 30-year-old man presenting with slight facial dysmorphisms, hypoparathyreoidism, minor cardiac anomalies, and slight cognitive impairments who had developed a severe personality disorder which eventually led to the diagnosis of microdeletion 22q11.2 with maternal inheritance. Psychiatric patients should be thoroughly examined for typical signs associated with this chromosomal anomaly. Genetic diagnosis is necessary because of the 50% probability of inheritance with possibly severe congenital anomalies. In view of a prevalence of 2% in an unselected group of patients with schizophrenic psychosis, microdeletion 22q11.2 is likely to be underdiagnosed.

Adult↗

PubMed1998

Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies.

UNLABELLED: Conotruncal malformations account for about 50% of congenital heart defects diagnosed in newborns. We studied prospectively 104 patients admitted in our neonatal intensive care unit for conotruncal defects by fluorescence in situ hybridization to estimate the prevalence of the interstitial deletion in this category of congenital heart disease. Cardiac phenotypes were: truncus arteriosus (17), interrupted aortic arch (18), tetralogy of Fallot with or without pulmonary valve atresia (55), tetralogy of Fallot with absent pulmonary valves (5), ventricular septal defect with malalignment of the conal septum (9). We discovered a microdeletion 22q11 at loci D22S39 or D22S398 in 50 newborns (48%). The prevalence of this microdeletion in different groups of conotruncal defects was: truncus arteriosus 7/17, interrupted aortic arch 16/18, tetralogy of Fallot 19/55, absent pulmonary valves 2/5, and ventricular septal defect 6/9 respectively. Only two patients without any clinical or biological feature of the so called CATCH22 syndrome exhibited the deletion. Parental studies confirmed that the deletion occurred de novo in 47/50 cases (three parental microdeletions). On the other hand, recurrence of conotruncal heart defects in families of "undeleted probands" was higher than expected (13%). CONCLUSION: In 50/104 newborns with conotruncal defects, an interstitial deletion 22q11 was found. Fluorescence in Situ Hybridization should be performed in newborn infants with conotruncal defect and at least one additional manifestation of the CATCH22 phenotype.

Chromosome Deletion↗

PubMed1997

Microdeletion 22q11 in complex cardiovascular malformations.

Besides DiGeorge, velocardiofacial and conotruncal anomaly face syndromes, some of the isolated congenital heart diseases have also been associated with a chromosomal deletion in 22q11. These disease entities, which had originally been considered to have a different genetic background, are now included in the CATCH-22 microdeletion complex. CATCH 22 is an acronym for cardiac defect, abnormal facies, thymic hypoplasia or aplasia and T-cell deficiency, cleft palate, hypoparathyroidism, and hypocalcemia. In the present study, we focused on the complex cardiovascular defects (CCVD) and screened 40 patients for a microdeletion of 22q11 by fluorescence in situ hybridization using the D22S75 DNA probe and for associated CATCH features. The patients were from genetic counseling (n = 15) or fetopathology (n = 3) of the Clinical Genetics Department in Marburg and from the Pediatric Cardiology Department (n = 22) in Mainz. Monosomy 22q11 was detected in 9 cases (= 22.5%). Familial transmission with one mildly affected parent and one affected sib each was proven in two cases. The CCVDs comprised complex conotruncal defects such as tetralogy of Fallot, double outlet right ventricle, transposition of great arteries and truncus arteriosus communis, or anomalies of the derivatives of the branchial arch arteries in association with a ventricular septal defect, including one case of atresia of the ductus arteriosus with pulmonary artery aneurysm and resulting in fetal hydrops. All 13 patients with a deletion of 22q11 showed at least one additional CATCH symptom. Most consistently, facial dysmorphy was apparent (92%), while hypocalcemia, mostly at threshold values, was present in 62% and thymic hypoplasia including borderline low T-lymphocyte numbers was observed in 41%. None of the patients presented with a cleft palate. A high intrafamilial variability in expression was also evident with respect to the CCVD. Our findings indicate that seemingly isolated complex cardiovascular defects associated with a 22q11 microdeletion most probably do not represent a distinct subgroup within the CATCH-22 complex but are syndromal in nature with extracardiac features that are often overlooked.

Adolescent↗

PubMedDate not supplied

AZF microdeletions on the Y chromosome of infertile men from Turkey.

Intervals V and VI of Yq11.23 regions contain responsible genes for spermatogenesis, and are named as "azoospermia factor locus" (AZF). Deletions in these genes are thought to be pathogenetically involved in some cases of male infertility associated with azoospermia or oligozoospermia. The aim of this study was to establish the prevalence of microdeletions on the Y chromosome in infertile Turkish males with azoospermia or oligozoospermia. We applied multiplex polymerase chain reaction (PCR) using several sequence-tagged site (STS) primer sets, in order to determine Y chromosome microdeletions. In this study, 61 infertile males were enrolled for the molecular AZF screening program. In this cohort, one infertile male had 46,XX karyotype and the remaining had 46,XY karyotypes. Forty-eight patients had a diagnosis of azoospermia and 13 had oligozoospermia. Microdeletions in AZFa, AZFb and AZFc (DAZ gene) regions were detected in two of the 60 (3.3%) idiopathic infertile males with normal karyotypes and a SRY translocation was determined on 46,XX male. Our findings suggest that genetic screening should be advised to infertile men before starting assisted reproductive treatments.

Chromosome Deletion↗

PubMed2004

Genetic aspects of human male infertility: the frequency of chromosomal abnormalities and Y chromosome microdeletions in severe male factor infertility.

OBJECTIVE: The main purpose of this study is to detect the frequency and type of both chromosomal abnormalities and Y chromosome microdeletions in patients with severe male factor infertility and fertile control subjects. The association between the genetic abnormality and clinical parameters was also evaluated. METHODS: This study was carried out in 208 infertile and 20 fertile men. Results of 208 patients, 119 had non-obstructive azoospermia and 89 had severe oligoasthenoteratozoospermia (OAT). Seventeen out of 119 (14.3%) azoospermic patients and two out of 89 (2.2%) patients with OAT had Y chromosome microdeletions. In total, 19 cases with deletions were detected in 208 infertile men, with a frequency of 9.1%. The AZFc locus, mainly DAZ gene cluster was the most frequently deleted region. Five other cases with azoospermia (4.2%) and two cases with OAT (2.2%) had a chromosomal abnormality, with a total number of seven (3.4%). Including Y chromosome deletions and structural chromosome abnormalities, the rate of genetic abnormalities was 12.5% (26/208) in our patients. On the other hand, 20 men with proven fertility and fathers of five cases with microdeletions were genetically normal. Y chromosome deletions and chromosomal abnormalities were associated with various histological alterations in testis. Sertoli cell-only (SCO) syndrome and maturation arrest predominated in these cases, whereas hypospermatogenesis occurred more frequently in genetically normal patients. CONCLUSION: Various chromosomal abnormalities and deletions of Y chromosome can cause spermatogenic breakdown resulting in chromosomally derived infertility. All these findings strongly support the recommendation of genetic screening of infertile patients.

Chromosome Deletion↗

PubMed2005

Two fast methods for detection of Y-microdeletions.

OBJECTIVE: To test two recently available commercial kits: the new Promega Y Chromosome Deletion Detection System 2.0 kit and the Bird-Set kits (Y Chromosome UE and Extension). DESIGN: A comparative technical study. SETTING: Male infertility clinic. PATIENT(S): Twelve various Y chromosome microdeleted patients were included in the present study: two AZFa deleted, two AZFb deleted, four AZFb+c deleted, three AZFc deleted, and one AZF a+b+c deleted. INTERVENTION(S): DNA samples were tested with both the Promega kit and the Bird-Set kits. MAIN OUTCOME MEASURE(S): Electrophoresis and analysis comparison on a bioanalyzer. RESULT(S): Both kits (Promega 2.0 and Bird Y Chromosome UE) confirmed the 12 Y deletions. Both kits (Bird Extension and Promega 2.0) were able to determine the length of the 12 microdeletions with various differences. The new Promega 2.0 kit was considerably improved, with the addition of two sequenced tag sites (STS) in AZFa (sY86 and sY84) and the deletion of some (sY239 and sY153) but not all supernumerary inadequate STS. CONCLUSION(S): The two new commercially available kits use two different protocols to detect Y chromosome microdeletions. The Promega kit is a one-step diagnostic test. The Bird diagnostic test uses a two-step protocol. Both kits offer relevant methods such as standardization and ready-to-use mixes. However, both kits need further evaluation under routine conditions using nontested DNA samples.

Chromosome Deletion↗

PubMed2004

[A simple, low-cost and non-invasive method for screening Y microdeletions in infertile men].

OBJECTIVES: Recent investigations showed a high prevalence of Y chromosome microdeletions in men with severely impaired spermatogenesis. Screening for these men is recommended prior to assisted reproduction techniques. The aim of this study was to set up a simple method to detect Y deletion in infertile men. First, we tested the feasibility of cytobrush to collect oral cells as source of DNA. Second, we compared a classic PCR corresponding to European recommendations to the Promega kit. PATIENTS AND METHODS: Seventeen infertile male patients with previously characterized deletions were included in the present study, after fully informed written consent. Both oral cells and blood were used for DNA extraction. A specific DNA extraction protocol was carried out on the buccal cells. The DNAs were tested for Y deletion screening by two different methods. RESULTS: We retrieved between 4 and 10 microg of DNA per brush from buccal cells, allowing several multiplex PCR. The Promega kit detected all the deletions but one: an AZFa deletion was not detected by the two markers of the kit covering this region. In addition, sY130, sY133 and SY153, included in the kit, are not reliable. DISCUSSION AND CONCLUSIONS: Buccal cells represent a convenient substitute for blood in testing for Y microdeletions. Both false negative and false positive results were obtained with Promega Kit. On the opposite, PCR according to the European recommendations allow the accurate detection of Y microdeletion in our 17 cases, at a lower cost.

Chromosomes, Human, Y↗

PubMed1999

Microdeletion of the DAZ (deleted in azoospermia) gene or the YRRM (Y chromosome ribonucleic acid recognition motif) gene does not occur in patients with Klinefelter's syndrome with and without spermatogenesis.

OBJECTIVE: To evaluate the occurrence of microdeletions of the Y chromosome involving the DAZ and YRRM genes in patients with Klinefelter's syndrome with and without spermatogenesis. DESIGN: Controlled clinical study. SETTING: Yamagata University Hospital, Yamagata, Japan. PATIENT(S): Patients with Klinefelter's syndrome with spermatogenesis (n = 1) and without spermatogenesis (n = 20) and a control group of men of proven fertility (n = 10). INTERVENTION(S): Blood and semen sampling and testicular biopsy. MAIN OUTCOME MEASURE(S): Semen analysis, polymerase chain reaction amplification of 32 DNA loci on the long arm of the Y chromosome involving the DAZ (deleted in azoospermia) and YRRM (Y chromosome ribonucleic acid recognition motif) genes, and measurement of plasma FSH, LH, and testosterone levels. RESULT(S): No microdeletions of 32 loci were found in any of the patients with Klinefelter's syndrome, either with or without spermatogenesis. Plasma LH and FSH levels were abnormally high and testosterone levels were reduced in all the patients with Klinefelter's syndrome. American Society for Reproductive Medicine.) CONCLUSION(S): Severe impairment of spermatogenesis in patients with Klinefelter's syndrome is not caused by microdeletions of the Y chromosome involving the DAZ and YRRM genes.

DNA↗

PubMed2000

A novel, rapid, and accurate method for detecting microdeletion involving the DAZ gene in infertile men.

OBJECTIVE: To report on a novel, accurate method for detecting microdeletion involving the DAZ gene in infertile men. DESIGN: Retrospective clinical study. SETTING: University Infertility Center of Cochin Hospital, Paris, France. PATIENT(S): Infertile patients (n = 25) consulting our infertility department during 1998. The patient cohort included subjects with nonobstructive azoospermia and oligoasthenospermia. INTERVENTION(S): Blood samples were collected from each subject. MAIN OUTCOME MEASURE(S): DNA analysis using polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). RESULT(S): We used a new molecular genetic strategy to rapidly identify deletions of the Y chromosome that include the DAZ locus. The experiment consists of amplifying simultaneously exon 4 of the DAZ and DAZLA genes with the use of specific primers that are complementary to intronic sequences of these genes. DGGE was used to separate the two PCR products, with good resolution. In infertile men with a microdeletion of the DAZ gene, this method allows amplification of an internal control when a deletion of that portion of the Yq chromosome is observed on a single amplification. CONCLUSION(S): This PCR-DGGE method for detection of DAZ gene deletion is simple and fast and does not require the use of radioactive elements. Compared with the classic PCR approach, this new method allows the amplification of the DAZLA copy to be used as an effective internal control in infertile men with microdeletion of the DAZ locus. This procedure could be particularly useful in screening for the DAZ locus in the diagnostic workup of nonobstructive azoospermia and severe oligoasthenoteratozoospermia.

Adult↗

PubMed1996

Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.

OBJECTIVES: To assess the incidence of microdeletions of chromosomal region 22q11 in a population of infants coming to a regional pediatric cardiac center with selected abnormalities of the ventricular outflow tracts and aortic arch and, further, to provide phenotypic/genetic correlations to determine whether patients with 22q11 deletions can be clinically recognized in infancy. BACKGROUND: DiGeorge syndrome and velocardiofacial syndrome are frequently associated with malformations of the ventricular outflow tracts and aortic arch. Both are usually caused by microdeletions of chromosomal region 22q11. The overall importance of such deletions as a cause of these cardiac malformations remains to be established. STUDY DESIGN: All infants with the candidate cardiac phenotypes during a 34-month period were studied. Dysmorphic features, type of cardiac defect, serum calcium concentration, and thymic status were recorded. Cytogenetic studies, including high-resolution karyotyping and fluorescence in situ hybridization using cosmids (cEO or cH748) from the DiGeorge critical region, were performed after clinical assessment. RESULTS: Fifty infants (including 36 with tetralogy of Fallot with or without pulmonary atresia) were seen during the study period. Twenty-six infants (52%) were dysmorphic, including 19 who were considered to have a phenotypic appearance consistent with 22q11 deletion. Genetic analysis confirmed hemizygosity for 22q11 in 8 of these 19 cases. Results of fluorescence in situ hybridization studies were normal in 22 infants without dysmorphic features and in 5 infants with dysmorphic features not suggestive of a 22q11 deletion. CONCLUSIONS: Microdeletions of chromosomal region 22q11 are an important cause of selected malformations of the ventricular outflow tracts and aortic arch and account for about 15% to 20% of cases. These deletions may be clinically recognized in early infancy and can be rapidly confirmed by fluorescence in situ hybridization.

Aorta, Thoracic↗

PubMed2000

Y chromosome microdeletions in infertile men with varicocele.

The pathogenic mechanisms by which varicocele disrupt spermatogenesis are not clearly understood and it is possible that when varicocele is associated with a severe bilateral testiculopathy, other causes may represent the actual aetiological factor. Since microdeletions in the Y chromosome long arm (Yq) have become in last years a major cause of male infertility, we perform a Yq microdeletion screening in infertile men with varicocele. We selected 40 patients with severe oligozoospermia (sperm count<5x10(6)/ml, group 1) and 80 with varicocele and mild oligozoospermia (sperm count 10-20x10(6)/ml, group 2). Deletions of Yq was observed in seven out of 40 patients (17.5%) of group 1, while no deletions were found in patients of group 2, suggesting that the bilateral testicular damage observed in patients of group 1 is due to the underlying genetic anomaly, and not to varicocele itself. The finding of a genetic aetiology in infertile men with varicocele suggests that in such patients a Yq microdeletion screening should be performed, both for a proper diagnosis and to avoid unnecessary treatments that will probably not improve the sperm count.

Biopsy, Needle↗

PubMed2001

Multiplex PCR for screening of microdeletions on the Y chromosome.

PURPOSE: The aim of this study was to develop a multiplex PCR protocol, which could be suitable for screening of microdeletions in the three azoospermia factor (AZF) regions on the Y chromosome. METHODS: In the screening protocol, 36 known sequence tagged site (STS) primer pairs were first tested in single PCR reactions and thereafter combined in multiplex PCR to test for specificity and sensitivity in order to develop a stable and reliable multiplex PCR assay to detect Y microdeletions. RESULTS: Of the 36 primers tested, 11 turned out not to be specific or produced PCR products that were too weak, and they were therefore not used in the multiplex PCR. The remaining 25 STSs were selected on the basis of their ability to be reproducibly amplified with each other using identical amplification conditions. Five multiplex sets, each consisting of five primer pairs, were established in the multiplex PCR setup. CONCLUSION: The multiplex PCR protocol presented in this study is an easy and reliable method for detection of Y chromosome microdeletions and could be used for screening of infertile men to allow genetic counseling about the risk of transmitting infertility from father to son.

DNA-Directed DNA Polymerase↗

PubMed2000

Y chromosome microdeletions in idiopathic azoospermia and non-mosaic type of Klinefelter syndrome.

The objective of this study was to elucidate the cause of the spermatogenic defect in idiopathic azoospermia and non-mosaic type of Klinefelter syndrome. Genomic DNAs from 9 cases of Korean idiopathic azoospermia and 6 of Korean non-mosaic type of Klinefelter syndrome were used for the detection of Y chromosome microdeletions by polymerase chain reaction using 60 primers. Microdeletions of the Y chromosome were found in 1 of 9 (11.1%) patients with idiopathic azoospermia, whereas none was deleted in non-mosaic type of Klinefelter syndrome. This result suggests that Y chromosome microdeletions could be one of the etiologic factors in idiopathic azoospermia.

Gene Dosage↗

PubMed2002

Absence of microdeletions in the Y chromosome in patients with Prader-Willi syndrome with cryptorchidism.

Unilateral or bilateral cryptorchidism is found in 80-100% of male patients with Prader-Willi syndrome (PWS). Recently, the relationship between Yq deletions and cryptorchidism has been assessed. However, the relationship between Yq deletions and PWS patients with cryptorchidism remains unclear. Polymerase chain reaction (PCR) amplification of 51 DNA loci encompassing all of the regions for azoospermia factor (AZF) of the Y chromosome, including the deleted in azoospermia (DAZ) and ribonucleic acid-binding motif (RBM) genes, were examined for microdeletions in 10 PWS males with cryptorchidism and 20 healthy control male subjects. No microdeletions of 51 loci were found in any of the PWS males. The present study therefore suggests that microdeletions in the AZF regions of the Y chromosome do not relate to the occurrence of cryptorchidism in PWS patients.

Adolescent↗

PubMed2002

False-positive Y-microdeletion result for a fertile male caused by an alteration under a PCR primer.

The pathogenic relationship between the presence of Y chromosomal microdeletions and male infertility is unclear. Nevertheless, a causal relationship is thought to be probable when loci are shown to be deleted in infertile males but are present in fertile males. Polymerase chain reaction (PCR) analysis of the Y chromosome is now routinely performed in the evaluation of the infertile male, although, until recently, there has been no consensus on how the diagnosis should be performed and which loci or markers should be analysed. The European Academy of Andrology (EAA) published guidelines for the molecular diagnosis of Y chromosomal microdeletions in 1999. Following these guidelines, our laboratory developed assays that incorporated the suggested primer pairs for the recommended Sequence Tagged Sites (STS). A number of fertile (n = 117), infertile (n = 17) and unknown samples (n = 20) were tested in our laboratory as part of the validation to provide a clinical assay. Two multiplex PCR assays were optimized, each of which examined STS markers in the centre of the AZFa, b and c regions of the Y chromosome. We correctly identified all but one of the 154 samples (according to the expected result based on fertility or previous testing at another laboratory). A single equivocal result was observed for a sample obtained from a known fertile male who appeared to be deleted for a single marker, sY84, in the AZFa region but not the adjacent marker, sY86. Follow-up analysis showed that proximal and distal markers within the same region (sY82 and sY98) were also present. Sequencing the region flanking and including the sY84 primer set revealed a single base alteration under the reverse primer, which probably caused the amplification failure. Furthermore, the sY84 sequence itself was present, as was the flanking sequence 50 bp on either side of both primers. This observation underlines the importance of using at least two closely linked STS markers for the reliable diagnosis of Y chromosome microdeletions as proposed by the EAA guidelines.

Base Sequence↗

PubMedDate not supplied

Natural transmission of AZFb Y-chromosomal microdeletion from father to his three sons.

Microdeletions of the so-called azoospermia factor (AZF) locus of the Y chromosome long arm (Yq) are an etiological factor of severe oligozoospermia or azoospermia. Patients affected are infertile unless assisted reproductive techniques are used. We report the case of an azoospermic patient (proband) and three brothers who inherited a Yq microdeletion from their father through a spontaneous pregnancy. Leukocyte DNA was extracted using a commercially available kit. A total of 15 pairs of sequence-tagged site (STSs) based primers, spanning the AZFa, b and c regions, were used for screening. All brothers and their father carried a Yq microdeletion of the AZFb subregion where the RNA-binding motif (RBM) gene is located. The proband carried additional deletions of the AZFa and AZFb subregions. RBM deletion can be associated with oligozoospermia allowing natural conception and therefore natural transmission of this genetic anomaly.

Adult↗

PubMed1998

Identification of microdeletions spanning the Diamond-Blackfan anemia locus on 19q13 and evidence for genetic heterogeneity.

Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to approximately 1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.

Chromosome Mapping↗

PubMed2003

Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome.

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.

Abnormalities, Multiple↗