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PubMed1997

Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.

We have analyzed a recently described 22q13.3 microdeletion in a child with some overlapping features of the cytologically visible 22q13.3 deletion syndrome. Patient NT, who shows mild mental retardation and delay of expressive speech, was previously found to have a paternal microdeletion in the subtelomeric region of 22q. In order to characterize this abnormality further, we have constructed a cosmid/P1 contig covering the terminal 150 kb of 22q, which encompasses the 130-kb microdeletion. The microdeletion breakpoint is within the VNTR locus D22S163. The cloning of the breakpoint sequence revealed that the broken chromosome end was healed by the addition of telomeric repeats, indicating that the microdeletion is terminal. This is the first cloned terminal deletion breakpoint on a human chromosome other than 16p. The cosmid/P1 contig was mapped by pulsed-field gel electrophoresis analysis to within 120 kb of the arylsulfatase A gene, which places the contig in relation to genetic and physical maps of the chromosome. The acrosin gene maps within the microdeletion, approximately 70 kb from the telomere. With the distal end of chromosome 22q cloned, it is now possible to isolate genes that may be involved in the overlapping phenotype of this microdeletion and 22q13.3 deletion syndrome.

Cell Line, Transformed↗
PubMed2001

Spontaneous microdeletions and microinsertions in a transgenic mouse mutation detection system: analysis of age, tissue, and sequence specificity.

A total of 3497 independent spontaneous mutations were examined using the Big Blue transgenic mouse mutation detection system. Base substitutions predominate, although 16% of somatic and germline mutations are microdeletions, microinsertions, or deletions combined with insertions. The pattern of microdeletions and microinsertions is similar in both the lacI transgene and the human p53 gene. Single-base deletions (D1) and insertions (I1) are evenly distributed in the lacI transgene, whereas microdeletions from 2 to 50 bp are clustered at two regions (bp 129-228 and 529-628). The pattern of microdeletions and microinsertions is similar between young (< or =3 months) and old (25 months) mice. Brain tissue has a paucity of deletions combined with insertions when compared with that of thymus and nine other tissues (P = 0.01). A 16-bp deletion at lacI base position 272 is a tissue-specific hotspot preferentially occurring in brain. Approximately 68 and 93% of D1 and I1, respectively, occur at mononucleotide repeats. The frequencies of D1 and I1 in mononucleotide repeats increase in an exponential manner with the length of the repeat. The lacI transgene shows similarity to the human p53 gene in the pattern of microdeletions and microinsertions and the size distribution of microdeletions.

Age Factors↗
PubMed2003

Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion.

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

Carrier Proteins↗
PubMed2004

Embryo outcome in Y-chromosome microdeleted infertile males after ICSI.

UNLABELLED: A prospective study involving 118 infertile Japanese couples to assess the embryo outcomes in both azoospermic and oligoasthenoteratoazoospermic (OAT) patients with Y-chromosome microdeletion. The men were divided into two groups; azoospermia (n = 27), and OAT, sperm concentration <5 x 10(6)/ml (n = 91). They were investigated for Y-chromosome microdeletions by a polymerase chain reaction (PCR) amplification of the Y-chromosome-specific sequence tag site (STS). The embryo outcomes of patients found to have Y-microdeletion were determined. The frequency of microdeletion was 8.8% (9) and two had microdeletions distal to DAZ. The mean fertilization rate and the cleavage rate in the eight cycles of both azoospermic and oligospermic patients were 59.3 and 87.5%, respectively. The percentages of grade 1 & 2 embryos, > or =6 cells embryos, and blastocyts were 51.7, 65.6, and 45.3%, respectively. Three pregnancies resulted from the eight cycles (37.5%). CONCLUSION: in Y-chromosome microdeletion cycles in which sperm cells were available for intracytoplasmic sperm injection (ICSI), embryo outcome was comparable to conventional IVF.

Biomarkers↗
PubMed1992

Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene.

For males with idiopathic sterility, a molecular screen specific for small lesions (microdeletions) in interval 6 of the Y chromosome was set up using 29 Y-DNA probes. A "de novo" microdeletion in Y interval 6 was detected in 2 out of 19 "chromosomally normal" sterile males. The first microdeletion includes the Y-DNA probes pY6HP35 and 12f3; the second microdeletion includes the Y-DNA probes pY6HP52, 49f, FR15-II and the subinterval "C" of probe 50f2. A probe of the pY6H sequence family is present in both deletions. Sequences of this family cross-hybridize to dhMiF1, a DNA sequence of a fertility gene structure on the Y chromosome of Drosophila hydei. It was possible to map the position of the Y-deletion of one patient to the distal part of Yq11.22 or the proximal part of Yq11.23, and the deletion of the second patient to the distal part of Yq11.23. These microdeletions probably do not overlap. Since AZF, a human spermatogenesis gene, has been mapped to Y interval 6, we postulate that the microdeletions detected in this chromosome region affect the functional DNA structure of the AZF gene. If this holds true, it is possible that the AZF locus, cytogenetically mapped to distal Yq11, contains two spermatogenesis genes (AZFa and AZFb) or a large gene structure comparable to the Y fertility genes of Drosophila.

Chromosome Deletion↗
PubMed2002

Transmission of Y chromosomal microdeletions from father to son through intracytoplasmic sperm injection.

We conducted chromosomal analysis of three male infants fathered by severe oligozoospermic males with Y chromosomal microdeletions through intracytoplasmic sperm injection (ICSI). Two of the infants had the same Y chromosomal microdeletions as their fathers. The third infant also had a Y chromosomal microdeletion, which was longer than that found in his father. The results confirm that Y chromosomal microdeletions are transmitted from a father to a son via ICSI and also suggest that the microdeletions may be expanded during such transmission. Genetic counseling for infertile couples contemplating ICSI is important if the male carries Y chromosomal microdeletions.

Cytoplasm↗
PubMed2004

AZF microdeletions of the Y chromosome and in vitro fertilization outcome.

OBJECTIVE: To determine whether the presence of a Y microdeletion confers any adverse effects on in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) outcome. DESIGN: Retrospective case-control study. SETTING: Academic infertility center. PATIENT(S): A total of 17 patients with Y microdeletions who attempted IVF/ICSI cycles at our center between March 1996 and March 2002 were studied. Study patients were analyzed in two groups: those who underwent testicular sperm extraction (TESE) and those for whom ejaculated sperm was used. INTERVENTION(S): The two patient study groups were matched to controls treated at the same time who had either nonobstructive severe oligozoospermia or azoospermia with normal Y chromosomes. Controls were matched for age of the female partner, sperm concentration, and number of embryos transferred. MAIN OUTCOME MEASURE(S): Fertilization and clinical pregnancy rates. RESULT(S): Sperm was only obtained from patients with azoospermic factor (AZF)c microdeletions (and from one patient with a partial AZFb microdeletion). A trend toward lower fertilization rates in patients with Y microdeletions was noted, which did not reach statistical significance. Clinical pregnancy rates per cycle and per transfer were similar to those for controls. CONCLUSION(S): Patients with AZFc microdeletions seem to have IVF/ICSI outcomes comparable to those of controls with normal Y chromosomes.

Case-Control Studies↗
PubMed1997

Microdeletions in the Y chromosome of infertile men.

BACKGROUND: Some infertile men with azoospermia or severe oligospermia have small deletions in regions of the Y chromosome. However, the frequency of such microdeletions among men with infertility in general is unknown. We sought to determine the prevalence of Y-chromosome microdeletions among infertile men and to correlate the clinical presentation of the men with specific deletions. METHODS: We studied 200 consecutive infertile men. Each man was evaluated comprehensively for known causes of infertility, and Y-chromosome microdeletions were studied with use of the polymerase chain reaction to amplify specific regions of the chromosome. The Y chromosomes of 200 normal men were also analyzed. RESULTS: Fourteen infertile men (7 percent) and four normal men (2 percent) had microdeletions of the Y chromosome. Nine of the infertile men had azoospermia or severe oligospermia (sperm concentration, <5 million per milliliter), four had oligospermia (sperm concentration, 5 million to <20 million per milliliter), and one had normospermia (sperm concentration, > or = 20 million per milliliter). The size and location of the deletions varied and did not correlate with the severity of spermatogenic failure. The fathers of six infertile men with microdeletions were studied; two had the same deletions as their sons, and four had no deletions. CONCLUSIONS: A small proportion of men with infertility have Y-chromosome microdeletions, but the size and position of the deletions correlate poorly with the severity of spermatogenic failure, and a deletion does not preclude the presence of viable sperm and possible conception.

Adult↗
PubMed2000

Unequal meiotic crossover: a frequent cause of NF1 microdeletions.

Neurofibromatosis type 1 is a common autosomal dominant disorder caused by mutations of the NF1 gene on chromosome 17. In only 5%-10% of cases, a microdeletion including the NF1 gene is found. We analyzed a set of polymorphic dinucleotide-repeat markers flanking the microdeletion on chromosome 17 in a group of seven unrelated families with a de novo NF1 microdeletion. Six of seven microdeletions were of maternal origin. The breakpoints of the microdeletions of maternal origin were localized in flanking paralogous sequences, called "NF1-REPs." The single deletion of paternal origin was shorter, and no crossover occurred on the paternal chromosome 17 during transmission. Five of the six cases of maternal origin were informative, and all five showed a crossover, between the flanking markers, after maternal transmission. The observed crossovers flanking the NF1 region suggest that these NF1 microdeletions result from an unequal crossover in maternal meiosis I, mediated by a misalignment of the flanking NF1-REPs.

Adolescent↗
PubMed2002

A cost-effective screening test for detecting AZF microdeletions on the human Y chromosome.

PCR-based screening of microdeletions in the azoospermic factor (AZF) on the Yq chromosome is an accepted means of identifying a common genetic cause of male infertility, responsible for 5-15% of cases associated with a low sperm count (</=5 x 10(6) sptz/ml). Based on an extensive analysis of the literature, we have established a cost-effective preliminary PCR-based diagnostic screening test, with a set of six pairs of primers ("set-of-6") that have the capability of detecting up to 95% of the Y microdeletion cases already published. These primers are: sY84 in AZFa, sY114, sY129, sY143 in AZFb, and sY149, sY254 in AZFc. Initially, the set-of-6 was tested with 13 other pairs of primers covering the three AZF subregions. A sample of 114 infertile men was tested and 10 (8.8%) microdeletions were found, 3 of which were among the 26 (11.5%) idiopathic azoospermic men. These results showed that all detected microdeletions would be identified using the set-of-6 only. Another sample of 34 patients was subsequently tested using the set-of-6 and 3 (8.8%) microdeletions were found in this group. A comparison of our results with those reported in the literature showed similar microdeletion detection frequencies, demonstrating that the set-of-6 primers provides a reliable, simple and cost-effective way of detecting AZF deletions.

Base Sequence↗
PubMed2004

Diagnostic test for Y chromosome microdeletion screening in male infertility.

Despite the current lack of understanding the mechanism of deleterious effects of Y chromosome microdeletions and their prognostic influence on male subfertility, the Y chromosome microdeletion test is widely used in the diagnostic evaluation of male subfertility. However, currently used diagnostic schemes have not been sufficiently evaluated for their diagnostic performance. The purpose of this study was to analyze a large database of published Y chromosome microdeletions to develop the optimal screening strategy for male subfertility. Therefore, we created a database from genetic and clinical data published in 52 peer-reviewed studies reporting on 512 cases with Y chromosome microdeletions. We developed a computerized procedure with the goal of minimizing the number of genetic markers included in the diagnostic set while maximizing the detection rate in patients with microdeletions. We estimate that 85.6% of all published Y chromosome microdeletions can be covered by a set of six genetic markers (sY84, sY127, sY152, RBMY1, sY147, sY254-DAZ). Inclusion of additional markers brings relatively little to the sensitivity of the test and is potentially related to the population origin.

Chromosome Deletion↗
PubMed2005

Y chromosome microdeletions: are they implicated in teratozoospermia?

BACKGROUND: Y chromosome microdeletions are known to impair spermatogenesis. Screenings for these microdeletions are performed mostly in patients with sperm count abnormalities. METHODS: We have screened the Y chromosome of 80 infertile patients with sperm morphological abnormalities. DNA from sperm, peripheral blood or single sperm following multiple displacement amplification (MDA) was utilized to amplify 20 specific sequence-tagged sites (STS) by PCR. RESULTS: Y chromosome microdeletions were detected in sperm DNA from four of the teratozoospermic patients; while none of the 53 men with normal sperm morphology had any deletions. Two of the four patients with deletions also provided peripheral blood and a fresh semen sample. Both patients had none of the STS deleted in the peripheral blood DNA. Y chromosome microdeletion analysis in the MDA amplified SRY-positive single sperm DNA confirmed the presence of the same deletion in all 10 sperm for one patient and eight out of 10 sperm in the second patient. CONCLUSIONS: Our observations suggest that some of the teratozoospermia might be related to gonadal mosaic Y chromosome microdeletions. Gonadal mosaicism can be a source of de novo transmissions of Y chromosome microdeletions. The application of MDA can yield enough DNA from a single sperm for genetic analyses.

Chromosome Deletion↗
PubMed2006

Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature.

Approximately 5% of patients with neurofibromatosis type 1 (NF1) have deletions of the entire NF1 gene. The phenotype usually includes early onset, large number of neurofibromas, presence of congenital anomalies, cognitive deficiency, and variable dysmorphic features and growth abnormalities. Connective tissue abnormalities are not generally recognised as a part of NF1 microdeletion syndrome, but mitral valve prolapse, joint laxity, and/or soft skin on the palms have been reported in a few patients. We describe clinical findings in six newly diagnosed patients with NF1 microdeletions, five of whom presented with connective tissue abnormalities. A literature review of the clinical findings associated with NF1 microdeletion was also performed. Our report confirms that connective tissue dysplasia is common in patients with NF1 microdeletions. Given the potential for associated cardiac manifestation, screening by echocardiogram may be warranted. Despite the large number (>150) of patients with known NF1 microdeletions, the clinical phenotype remains incompletely defined. Additional reports of patients with NF1 microdeletions, including comprehensive clinical and molecular information, are needed to elucidate possible genotype-phenotype correlation.

Adolescent↗
PubMed2003

Positional identification of microdeletions with genetic markers.

The positional identification of genetic factors for both simple and complex diseases is difficult. There is increasing evidence that small deletions are a fairly common cause for many genetic diseases and some complex diseases. To date, no statistical basis has been available for the identification of microdeletions in family studies. Here, we present an approach to the identification of novel microdeletions for parent-affected offspring trios. We present several different approaches that can be applied to identify microdeletions and also evaluate the statistical behavior of one of these methods in simulated data. The results show that for the study of single nucleotide polymorphisms, the error rate has an approximately linear effect in decreasing the ability to identify microdeletions. On the other hand, heterogeneity of causation, with only some families showing a microdeletion had a more severe influence upon the ability to identify de novo microdeletions.

Chromosome Mapping↗
PubMed2005

Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome.

BACKGROUND: Endocrine abnormalities, including hypocalcemia, thyroid dysfunction, and short stature, are associated with chromosome 22q11.2 microdeletion syndrome. This study was undertaken to examine the frequencies and clinical features of endocrine abnormalities in patients with 22q11.2 microdeletion syndrome. METHODS: We analyzed 61 patients with 22q11.2 microdeletion syndrome diagnosed based on the verification of microdeletion by fluorescent in situ hybridization (FISH) using a probe of the DiGeorge syndrome critical region (TUPLE1) at 22q11.2 and a control probe, ARSA at 22q13. Serum total calcium, phosphorus, and intact parathyroid hormone (PTH) levels were measured, thyroid function test was performed, and serum IGF-1 and IGFBP-3 levels were also estimated. Height and weight of patients were compared with individual chronological ages. RESULTS: Hypocalcemia was found in 20 patients (32.8%), and overt hypoparathyroidism in 8 (13.1%). Two patients (3.3%) showed autoimmune thyroid diseases, 1 each with Graves' disease and Hashimoto thyroiditis. Ten patients (16.4%) were below the third percentile in height, but the serum IGF-1 level was normal in 9 out of these 10 patients. CONCLUSION: Our findings show that patients with chromosome 22q11.2 microdeletion syndrome present with variable endocrine manifestations and variable clinical phenotypes. In addition to FISH analysis, careful endocrine evaluations are required in patients with this microdeletion syndrome, particularly for those with hypoparathyroidism or thyroid dysfunction.

Body Height↗
PubMed1999

Y chromosome microdeletions in cryptorchidism and idiopathic infertility.

To clarify whether cryptorchidism might be the expression of an intrinsic congenital testicular abnormality, we investigated the frequency of Y chromosome long arm (Yq) microdeletions in unilateral excryptorchid subjects manifesting an important bilateral testiculopathy. Microdeletion analysis of Yq was performed by polymerase chain reaction in the following subjects: 40 unilateral excryptorchid patients with azoospermia or severe oligozoospermia due to a bilateral severe testiculopathy (Sertoli cell-only syndrome or severe hypospermatogenesis); 20 unilateral excryptorchid men with moderate oligozoospermia and a normal testicular cytological picture in the contralateral testis; 110 patients affected by idiopathic severe primary testiculopathies; 20 patients affected by idiopathic moderate testiculopathy; and, as controls, 50 patients affected by known causes of testiculopathy and 100 fertile men. Eleven of 40 (27.5%) unilateral excryptorchid patients affected by bilateral testiculopathy and 28 of 110 (25.4%) patients affected by idiopathic severe primary testiculopathy showed Yq microdeletions, whereas no microdeletions were found in all the other subjects, nor in male relatives of patients with deletions. Microdeletions were located in different parts of Yq, including known regions involved in spermatogenesis (DAZ and RBM, AZFa, b, and c) and other loci still poorly defined. No difference in localization of deletions was evident between cryptorchid and idiopathic patients. Microdeletions in Yq may be responsible for severe bilateral testicular damage that could be phenotypically expressed by unilateral cryptorchidism, as well as by idiopathic infertility.

Adult↗
PubMed2001

Sertoli cell function in infertile patients with and without microdeletions of the azoospermia factors on the Y chromosome long arm.

Deletions of the azoospermia factors on the Y chromosome long arm are an important cause of male infertility, and they may involve germ cell-specific genes or ubiquitously expressed genes. To date, no clinical or hormonal parameters have yet been found to distinguish patients with and without Yq microdeletions. In particular, Sertoli cell function, as evaluated by inhibin B, has not yet been described. Our hypothesis was that microdeletions involving genes specifically expressed in germ cells should not alter Sertoli cell function. To do this, we have evaluated the testicular hormonal function in infertile patients affected by severe testiculopathies with and without Yq microdeletions, with particular emphasis on Sertoli cell function. We studied 102 well-characterized infertile patients; 27 had Yq microdeletions, and 75 were classified as idiopathic infertiles. Patients with Yq microdeletions had lower FSH and higher inhibin B plasma concentrations with respect to patients without microdeletions, suggesting that Sertoli cell function in Yq-deleted men is only partially altered. Furthermore, patients with deletions involving germ cell-specific genes had higher concentrations of inhibin B with respect to patients with deletions of ubiquitously expressed genes. These results suggested that a specific alteration of germ cells only partially influences Sertoli cell function. Hormonal status of patients without deletions suggested that in such cases the cause that has determined the spermatogenic defect may have damaged both Sertoli and germ cells. Inhibin B production in patients with Yq deletions was about 70% higher than the nondeleted patients, and the functional relationship between FSH and inhibin B was normally preserved. This study elucidated the multifactorial mechanisms underlying spermatogenic defects, where Sertoli cells may be normally functioning or damaged depending on the primary cause that has determined the testicular damage.

Chromosome Mapping↗
PubMed1999

Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans.

There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the beta-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the alpha-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA is a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate >300 mg/g creatinine). To investigate the role of the alpha-globin gene microdeletion and beta-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four alpha-globin genes (alpha-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact alpha-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and beta-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with alpha-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four alpha genes (86+/-2 versus 99+/-3 fl, and 33.9+/-0.2 versus 34.9+/-0.2%, respectively, P<0.05). There were no such hematologic differences between CAR and non-CAR beta-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87+/-1 mm Hg) in patients with intact alpha gene locus versus those with microdeletions (80+/-2 mm Hg, P<0.05). It is concluded that the coinheritance of microdeletions in the alpha-globin gene locus in SSA patients confers "renoprotection" by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.

Adult↗