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PubMed1998

A quarter of men with idiopathic oligo-azoospermia display chromosomal abnormalities and microdeletions of different types in interval 6 of Yq11.

Cytogenetic investigations and molecular analysis of the Y chromosome by the polymerase chain reaction amplification of sequence-tagged sites (STS-PCR) technique were performed in 126 patients affected by idiopathic oligo-azoospermia following accurate selection of cases. Seventeen patients evidenced an abnormal karyotype. Fourteen patients with a normal karyotype had microdeletions of the Y chromosome within interval 6. In azoospermic patients microdeletions were scattered along different subintervals, while in oligozoospermic patients they were clustered in subinterval 6E. The size of the deletion was not apparently related to the severity of the disease. These results suggest that cytogenetic analysis and the STS-PCR technique can detect a genetic cause of infertility in about one-quarter of patients with idiopathic oligo-azoospermia.

Adult↗
PubMedDate not supplied

Allelic variations at the haploid TBX1 locus do not influence the cardiac phenotype in cases of 22q11 microdeletion.

Microdeletion at the 22q11 locus is characterised by a high clinical variability. Congenital heart defects (CHD) are the most life-threatening manifestations of the syndrome and affect approximately 50% of patients carrying the deleted chromosome 22. The causes of this phenotype variability remain unknown although several hypotheses have been raised. It has been suggested that allelic variations at the haploid locus could modify the phenotypic expression. Regarding this hypothesis, TBX1 was thought to be a major candidate to the cardiac phenotype or its severity in patients carrying the 22q11 microdeletion. A mutational screening was performed in this gene, in a series of 39 deleted patients, with and without CHD. The results indicate that mutations in TBX1 are not likely to be involved in the cardiac phenotype observed in del22q11 patients.

Alleles↗
PubMed2006

PCR screening for 22q11.2 microdeletion: development of a new cost-effective diagnostic tool.

BACKGROUND: Del22q11.2 syndrome is the most frequent known chromosomal microdeletion syndrome. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. The molecular diagnosis of Del22q11.2 is usually made by fluorescence in situ hybridization, an expensive and not widely available technique. We developed an efficient and cost-effective PCR SNP assay designed for the screening of 22q11.2 deletion through consecutive homozygosity. METHODS: Through the screening of dbSNP we have selected SNP markers located in the 22q11.2 microdeleted region. Population heterozygosities were determined in 213 normal individuals. Designed assays consisted of PCR amplification followed by restriction enzyme digestion. Fragments generated were visualized on agarose gel and genotyped. RESULTS: Selected markers were: rs5748411, rs2238778, rs4819523 and rs4680. All selected markers were localized in the 22q11.2 deleted region. Allele and genotype frequencies of all selected markers were under Hardy-Weinberg equilibrium. Selected SNPs were not in linkage disequilibrium. Predicted assay specificity was estimated to be 92.86% in the Brazilian population. CONCLUSIONS: The use of consecutive homozygosity in this SNP-based diagnostic test may be used as a cost-effective tool in reference molecular genetics laboratories.

Adult↗
PubMed2005

High frequency of Y chromosome microdeletions in idiopathic azoospermic men with high follicle-stimulating hormone levels.

Y chromosome microdeletions were detected in 33.3% (6 out of 18) of idiopathic azoospermic patients with high serum follicle-stimulating hormone (FSH) levels in the present study. The results suggest that it may be necessary to detect microdeletions in patients with azoospermia, especially for those with high serum FSH levels, before assisted reproductive technology (ART) is provided to them.

Adult↗
PubMed2006

Reevaluation of azoospermic factor c microdeletions using sequence-tagged site markers with confirmed physical positions from the GenBank database.

OBJECTIVE: To investigate microdeletions and palindrome complexes in the azoospermic factor (AZF) c regions of the Y chromosome, by polymerase chain reaction (PCR) with sequence-tagged site (STS) markers with known physical positions, after verification of the exact physical locations of candidate STSs and exclusion of those that would give ambiguous results on PCR. DESIGN: Retrospective STS deletion study in infertile Japanese men. SETTING: University hospital and reproductive clinic. PATIENT(S): A total of 410 men with nonobstructive azoospermia and severe oligospermia (sperm concentrations of <5 x 10(6)/mL). INTERVENTION(S): Polymerase chain reaction was performed for all STS markers confirmed to be physically located in the partial AZFb and AZFc regions of the Y chromosome. All STSs were retrieved from the University of California at Santa Cruz database, and their location and specificity were verified. MAIN OUTCOME MEASURE(S): Presence or absence of appropriately sized PCR products. RESULT(S): Sixty-nine markers were retrieved, 32 of which were not specific to the long arm of the Y chromosome (Yq). The markers retained for test use were contiguous deletions classified as P1+P2 (AZFc) or P3 proximal/P1 (AZFb+c). The prevalence of accurately mapped microdeletions was 5.1% (21 of 410) in this patient population. CONCLUSION(S): Although noncontiguous deletions were observed, considerable confusion remained until the genome sequence was finally determined because many of the STSs were either repetitive sequences or polymorphic between individuals or races.

Animals↗
PubMed2006

Intracytoplasmic sperm injection may lead to vertical transmission, expansion, and de novo occurrence of Y-chromosome microdeletions in male fetuses.

Y-chromosome microdeletion in male fetuses conceived by intracytoplasmic sperm injection (ICSI) was screened by polymerase chain reaction for sequence-tagged sites in azoospermia factor (AZF)-b and AZFc regions. Treatment with ICSI may lead to vertical transmission, expansion, and de novo Y-chromosome microdeletion in male fetuses.

Chromosome Deletion↗
PubMedDate not supplied

Communication disorders in the 22Q11.2 microdeletion syndrome.

The 22q11.2 microdeletion syndrome is a genetic disorder that is being recognized with increasing frequency. Confirmation of the diagnosis can be made using fluorescence in situ hybridization. Many medical and developmental problems are present in children with this syndrome. Communication disorders are among the most common features of this syndrome and include articulation, language, resonance, and voice problems. The purpose of this paper is to provide a description of the communicative and developmental features in a sample of children with the 22q11.2 microdeletion syndrome seen for evaluation. Because communication and feeding disorders may be presenting features of this syndrome, speech and language pathologists must be familiar with this syndrome and its various characteristics. Awareness of these features and a multidisciplinary approach are necessary for the identification and treatment of the complex communicative and medical problems present in this population.

Adolescent↗
PubMed1999

Psychoeducational profile of the 22q11.2 microdeletion: A complex pattern.

OBJECTIVES: To examine the psychoeducational profile associated with the chromosome 22q11.2 microdeletion (DiGeorge/velocardiofacial syndrome). STUDY DESIGN: Thirty-three patients (aged 6 to 27 years) with a 22q11.2 microdeletion underwent psychoeducational testing as part of a comprehensive evaluation. Nonparametric statistics were used to compare verbal and performance IQ, academic achievement scores, and receptive versus expressive language scores. Post hoc comparisons were made of IQ subtest scores and of language versus verbal IQ. RESULTS: Full-scale IQ ranged from the normal to the moderately retarded range. Mean verbal IQ was significantly higher than mean performance IQ. In a similar manner, mean reading and spelling scores were superior to the mean mathematics score, although achievement scores typically were in the range of verbal IQ. In addition, many children showed clinically significant language impairments, with mean language scores lower than mean verbal IQ. CONCLUSIONS: The IQ and academic profiles are reminiscent of a "nonverbal learning disability," although achievement was not discrepant from IQ. The coincidence of language impairment with a relative strength in reading belies a unique neuropsychologic profile. Educational programming for these children must address both verbal and nonverbal deficits.

Adolescent↗
PubMed2002

[Male infertility and microdeletions of the Y chromosome].

It is estimated that about 10% of men suffer from male infertility. Male infertility is associated with a reduction in the quantity, reduced mobility or abnormal morphology of sperm. In about 50-60% of cases the etiology can be identified. When the cause is unknown, it is referred to as idiopathic infertility. A genetic cause is suspected in some of the latter cases since chromosome anomalies and familial forms of male infertility have been reported. Three different regions of the Y chromosome, termed AZFa, AZFb and AZFc are recurrently deleted in about 15% of cases of idiopathic azoospermia or severe oilgozoospermia. AZFc deletions form the majority of these deletions. The presence of a Y microdeletion does not seem to alter the fertilisation of the oocyte or the development of the embryo. However, if the child is a boy, he will inherit the deletion from his father and will most likely be infertile when he is an adult. In the absence of any other information concerning an association between Y chromosome microdeletions and other development anomalies of the child, in genetic counselling the principal risk for male offspring appears to be infertility.

Diagnosis, Differential↗
PubMed1999

A microdeletion syndrome due to a 3-Mb deletion on 19q13.2--Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation.

We report on a boy with congenital pure red blood cell aplasia [Diamond Blackfan anemia (DBA)] and severe congenital hypotonia, macrocephaly, hypertelorism, a broad and tall forehead, medial epicanthus, and facial hypotonia with mouth-breathing and drooling, an affable and out-going personality, and a general psychomotor retardation. These features show similarity to the phenotype of the X-linked FG syndrome. DBA was diagnosed at the age of 4 months, and the boy underwent treatment with transfusion and with prednisolone. He had a normal 46, XY karyotype, but fluorescence in situ hybridization (FISH) analysis to metaphase chromosomes revealed a 3-Mb deletion on 19q13.2. This chromosomal region has previously been linked to the DBA phenotype and one 19q13 microdeletion has been identified in a patient with DBA. This deletion coincides with the deletion reported here. We suggest that the complex phenotype of our patient, including both DBA and the associated features, represent a microdeletion syndrome.

Chromosome Deletion↗
PubMed2000

Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion.

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.

Abnormalities, Multiple↗
PubMed2004

Molecular characterization of an 11q14.3 microdeletion associated with leukodystrophy.

Leukodystrophies represent a heterogeneous group of rare hereditary diseases affecting the central nervous system. The underlying molecular defect remains unknown in almost 50% of cases. We previously assigned a new locus for leukodystrophy of unknown cause to chromosome 11q14.3 by identifying a de novo microdeletion in a sporadic case. We now report the precise molecular characterization of this microdeletion. Physical mapping of the region of interest allowed us to identify and analyze candidate gene(s) possibly implicated in leukodystrophy.

Cathepsin C↗
PubMed2006

Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation.

In contrast to the numerous well-known microdeletion syndromes, only a few microduplications have been described, and this discrepancy may be due in part to methodological bias. In order to facilitate the detection of genomic microdeletions and microduplications, we developed a new assay based on QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) able to explore simultaneously 12 candidate loci involved in mental retardation (MR) and known to be the target of genomic rearrangements. We first screened 153 patients with MR and facial dysmorphism associated with malformations, or growth anomalies, or familial history, with cytogenetically normal chromosomes, and the absence of FRAXA mutation and subtelomeric rearrangements. In this series, we found a 5q35 deletion removing the NSD1 gene in a patient with severe epilepsy, profound MR and, retrospectively, craniofacial features of Sotos syndrome. In a second series, we screened 140 patients with MR and behaviour disturbance who did not fulfil the de Vries criteria for subtelomeric rearrangements and who had a normal karyotype and no detectable FRAXA mutation. We detected a 22q11 deletion in a patient with moderate MR, obesity, and facial dysmorphism and a 4 Mb 17p11 duplication in a patient with moderate MR, behaviour disturbance, strabismus, and aspecific facial features. This new QMPSF assay can be gradually upgraded to include additional loci involved in newly recognised microduplication/microdeletion syndromes, and should facilitate wide screenings of patients with idiopathic MR and provide better estimates of the microduplication frequency in the MR population.

Child, Preschool↗
PubMed2001

Molecular detection of Y chromosome microdeletions: an Irish study.

The region of the Y chromosome most critical for male fertility is called the azoospermia factor (AZF) region and it is located within subintervals five and six on the long arm of the Y chromosome. Several genes, all residing here, contribute to spermatogenesis and 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 in the AZF region of the Y chromosome in an Irish male population undergoing fertility treatment. To do this, we applied and compared two independent polymerase chain reaction (PCR) based screening methods, namely, a PCR protocol using several sequence-tagged site (STS) primer sets and a recently published multiplex PCR Y chromosome screening protocol. A total of 78 patients, attending the IVF unit at University College Hospital, Galway, were included in this study. Of them, 56 suffered from idiopathic azoospermic/oligozoospermic infertility. The remaining 22 patients had various conditions, which may have contributed to their infertility. A total of 50 age-matched normospermic men were included as controls. Two microdeletions were found; one in the AZFa region and one in AZFb region. These deletions were observed among the truly idiopathic cases. Further analysis was performed to study the extent of the deletions and it was confirmed that each deletion encompassed the respective AZF region including the AZF candidate gene.

Adult↗
PubMed2005

Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19/IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.

Base Sequence↗
PubMed1998

Y chromosome microdeletions and male infertility.

Classical cytogenetic mapping has identified a locus on the long arm of the human Y chromosome that is required for spermatogenesis and is termed AZF, an acronym for the hypothetical azoospermia factor encoded by this locus. Recent molecular attempts to identify the gene corresponding to this locus have revealed that there are at least three genes in three separate microdeletion intervals. Two of these microdeletion intervals contain genes encoding proteins with potential roles in RNA metabolism. These genes are members of Y-encoded gene families with autosomal homologues. The cell biology of one of these genes, RBM (an acronym of RNA binding motif), is complex and suggests a role in pre-mRNA splicing.

Journal Article↗
PubMed2002

A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly.

Studies in mouse and chick have shown that the 5' HoxD genes play major roles in the development of the limbs and genitalia. In humans, mutations in HOXD13 cause the dominantly inherited limb malformation synpolydactyly (SPD). Haploinsufficiency for the 5' HOXD genes has recently been proposed to underlie the monodactyly and penoscrotal hypoplasia in two children with chromosomal deletions encompassing the entire HOXD cluster. Similar deletions, however, have previously been associated with split-hand/foot malformation (SHFM), including monodactyly. Here we report a father and daughter with SPD who carry a 117-kb microdeletion at the 5' end of the HOXD cluster. By sequencing directly across the deletion breakpoint, we show that this microdeletion removes only HOXD9-HOXD13 and EVX2. We also report a girl with bilateral split foot and a chromosomal deletion that includes the entire HOXD cluster and extends approximately 5 Mb centromeric to it. Our findings indicate that haploinsufficiency for the 5' HOXD genes causes not SHFM but SPD and point to the presence of a novel locus for SHFM in the interval between EVX2 and D2S294. They also suggest that there is a regulatory region, upstream of the HOXD cluster, that is responsible for activating the cluster as a whole.

Base Sequence↗