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At least 271 records · Page 15Linked to original sources
PubMed1999

Kabuki make-up syndrome is not caused by microdeletion close to the van der Woude syndrome critical region at 1q32-q41.

We reported on a 5-year-old Japanese girl with clinical manifestations of Kabuki make-up syndrome (KMS) and van der Woude syndrome (VWS). Since the concurrence of the two syndromes is known in four patients, including ours, it suggests a common cause. Assuming that the association of the two syndromes was caused by a microdeletion involving the putative KMS/VWS genes, we carried out fluorescence in situ hybridization and microsatellite analyses using PAC clones and dinucleotide repeat markers spanning the VWS1 critical region at 1q32-q41. No deletion was detected at the VWS1 critical region.

Abnormalities, Multiple↗
PubMed1996

Microdeletion and microduplication syndromes.

Microdeletions or microduplications have been shown to be associated with a number of important clinical conditions. In most cases no single gene within the segment has been identified as giving rise to the phenotype. The chromosomal rearrangements are generally too small to be identified reliably by standard cytogenetics, but a combination of FISH and molecular methods may be used. This review discusses the application of current knowledge to the prenatal diagnosis of the most common of these conditions i.e. Prader-Willi syndrome, Angelman syndrome, hereditary motor and sensory neuropathy type 1 and 22q11 deletion syndromes.

Angelman Syndrome↗
PubMed2001

Bernard-Soulier syndrome associated with 22q11.2 microdeletion.

We describe a Japanese girl with Bernard-Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder.

Abnormalities, Multiple↗
PubMed2004

Dysplastic changes in the peripheral blood of children with microdeletion 22q11.2.

Myelodysplasia refers to abnormal morphology of the bone marrow and/or peripheral blood. This condition is frequently due to myelodysplastic syndrome; however, myelodysplasia is caused by a variety of factors and is not always a sign of pre-malignant disease. We observed myelodysplastic changes in peripheral blood smears and bone marrow specimens from a patient who had chromosomal microdeletion 22q11.2 (del22q11.2). We then investigated such changes in several other patients who were newly diagnosed with del22q11.2 (n = 5 total, including the index case) and compared the findings to those in four sets of controls without this chromosomal abnormality. Specifically, the controls were children with conotruncal heart defects (n = 3); otherwise healthy children with bacterial (n = 4) or viral infection (n = 4); and healthy children (n = 4). The myelodysplasia scores in the myeloid cells and eosinophils of the children with del22q11 were higher than those in all four of the control groups. Myelodysplastic changes in the peripheral blood of children with del22q11.2 have not been reported previously. We believe that certain gene(s) in the deleted region may be responsible for the myelodysplastic changes that we observed in our patients with this chromosomal abnormality.

Bone Marrow↗
PubMed2002

Interstitial microdeletion of chromosome 1p in two siblings.

Two half-siblings are described with what we believe to be the second and third cases identified of the microdeletion, del(1)(p32.1p32.3). Both siblings had a tethered cord and had mental retardation, but otherwise their phenotypic presentations were quite different. The sister had failure to thrive, congenital dysplasia of the hip, absent corpus callosum, Chiari I malformation, and syringomyelia. The brother experienced neonatal seizures secondary to a hemorrhagic stroke. He had an accessory thumb, inguinal hernia, cryptorchidism, urinary reflux, and cholelithiasis. Although these children have only delayed development in common with the previously reported case, they help to further define chromosomal deletions in this area of chromosome 1. As yet, no clear phenotypic picture has emerged.

Adolescent↗
PubMed1992

Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes.

Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

Adolescent↗
PubMed1992

Xp22.3 microdeletion syndrome with microphthalmia, sclerocornea, linear skin defects, and congenital heart defects.

We report on an infant girl with congenital erythematous, linear skin lesions on face and neck, bilateral microphthalmia, sclerocornea, cataracts, and a complex cardiac anomaly including atrial septal and ventricular septal defects. This patient had an Xp22.3 microdeletion and a chromosome satellite on the abnormal X p-arm. The abnormal X chromosome was late replicating in peripheral blood lymphocytes and cultured skin fibroblasts. Four other patients with similar congenital anomalies and Xp deficiency have been reported previously and are compared with this patient. One patient had an interstitial or terminal deletion, but in others the material translocated to Xp22.3 was variable (Yq material in two patients, and Yp material and an unidentifiable satellite in one patient each). Several mechanisms are suggested by which this chromosome abnormality might produce this phenotype in these patients. Our patient is the first with this syndrome to have a congenital heart defect.

Abnormalities, Multiple↗
PubMed1993

Mental retardation locus in Xp21 chromosome microdeletion.

Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter - Aland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females.

Adrenal Glands↗
PubMed1995

Rapid molecular cytogenetic analysis of X-chromosomal microdeletions: fluorescence in situ hybridization (FISH) for complex glycerol kinase deficiency.

Diagnosis of X-chromosomal microdeletions has relied upon the traditional methods of Southern blotting and DNA amplification, with carrier identification requiring time-consuming and unreliable dosage calculations. In this report, we describe rapid molecular cytogenetic identification of deleted DNA in affected males with the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency, CGKD) and female carriers for this disorder. CGKD deletions involve the genes for glycerol kinase, Duchenne muscular dystrophy, and/or adrenal hypoplasia congenita. We report an improved method for diagnosis of deletions in individuals with CGKD and for identification of female carriers within their families, using fluorescence in situ hybridization (FISH) with a cosmid marker (cosmid 35) within the glycerol kinase gene. When used in combination with an Xq control probe, affected males demonstrate a single signal from the control probe, while female carriers demonstrate a normal chromosome with two signals, as well as a deleted chromosome with a single signal from the control probe. FISH analysis for CGKD provides the advantages of speed and accuracy for evaluation of submicroscopic X-chromosomal deletions, particularly in identification of female carriers. In addition to improving carrier evaluation, FISH will make prenatal diagnosis of CGKD more readily available.

Chromosome Mapping↗
PubMed2001

Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders.

Velo-cardio-facial syndrome (VCFS) is a congenital malformation syndrome with variable phenotypic features that has been associated with chromosomal microdeletion 22q11.2. Psychiatric disorders have been reported to be highly prevalent in individuals with this syndrome, and the objective of this study was to assess the nature and extent of psychopathology among individuals with VCFS. We studied 20 children and adolescents with 22q11 deletions determined by fluorescence in situ hybridization (FISH). Control subjects were 11 nondeleted siblings who were the closest age match to the affected subjects. Both affected and control subjects were assessed using two standardized psychiatric research instruments. The results of this study confirmed the high rate of psychiatric disorders among VCFS subjects (60% of our subjects). Of the specific types of disorders, only mood disorders were significantly more common among VCFS subjects compared to sibling controls, with eight VCFS subjects having mood disorders compared with none of the control subjects (P<0.02). Three affected subjects had schizotypal traits comorbid with a mood disorder. In addition, disruptive behavior disorders were frequently diagnosed among VCFS subjects. Using a dimensional measure of psychopathology, significant differences between VCFS subjects and sibling controls were found on three scales: ADHD (P<0.02), separation anxiety (P<0.02), and depression (P<0.01). VCFS subjects were achieving significantly less well academically and requiring significantly more special educational assistance than sibling controls. Follow-up data were available on two subjects, both of whom had been diagnosed with schizophrenia. Further research on psychopathology in VCFS may provide a model of how a specific genetic defect can lead to the development of psychiatric disorders.

Abnormalities, Multiple↗
PubMed2005

Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome.

Deletion of distal 6p is associated with a distinctive clinical phenotype including Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. We report the case of a child where recognition of the specific ocular and facial phenotype, led to identification of a 6p microdeletion arising from a de novo 6:18 translocation. Detailed analysis confirmed deletion of the FOXC1 forkhead gene cluster at 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delay. Unlike previous reports, hearing was normal.

Abnormalities, Multiple↗
PubMed2006

Delineation of a 2.2 Mb microdeletion at 5q35 associated with microcephaly and congenital heart disease.

Fine mapping of chromosomal deletions and genotype-phenotype comparisons of clinically well-defined patients can be used to confirm or reveal loci and genes associated with human disorders. Eleven patients with cytogenetically visible deletions involving the terminal region of chromosome 5q have been described, but the extent of the deletion was determined only in one case. In this study we describe a 15-year-old boy with Ebstein anomaly, atrial septal defect (ASD), atrioventricular (AV) conduction defect, and microcephaly. He had an apparently balanced paracentric inversion of chromosome 5, with the karyotype 46, XY,inv(5)(q13q35) de novo. Further mapping of the chromosome breakpoints using fluorescence in situ hybridization (FISH) revealed a 2.2 Mb microdeletion at the 5q35 breakpoint, which spans 16 genes, including the cardiac homeobox transcription factor gene NKX2-5. The current data suggest that haploinsufficiency of NKX2-5 cause Ebstein anomaly and support previous results showing that NKX2-5 mutations cause ASD and AV conduction defect. Furthermore, we suggest presence of a new microcephaly locus within a 2.2 Mb region at 5q35.1-q35.2.

Abnormalities, Multiple↗
PubMed1998

Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease.

An out-of-frame mutation of the mitochondrial DNA-encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron-like degeneration. The mutation is a heteroplasmic 5-bp microdeletion located in the 5' end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease (MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by-product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.

Adult↗
PubMed2002

Localization of the 17q breakpoint of a constitutional 1;17 translocation in a patient with neuroblastoma within a 25-kb segment located between the ACCN1 and TLK2 genes and near the distal breakpoints of two microdeletions in neurofibromatosis type 1 patients.

We have constructed a 1.4-Mb P1 artificial chromosome/bacterial artificial chromosome (PAC/BAC) contig spanning the 17q breakpoint of a constitutional translocation t(1;17)(p36.2;q11.2) in a patient with neuroblastoma. Three 17q breakpoint-overlapping cosmids were identified and sequenced. No coding sequences were found in the immediate proximity of the 17q breakpoint. The PAC/BAC contig covers the region between the proximally located ACCN1 gene and the distally located TLK2 gene and SCYA chemokine gene cluster. The observation that the 17q breakpoint region could not be detected in any of the screened yeast artificial chromosome libraries and the localization of the 17q breakpoint in the vicinity of the distal breakpoints of two microdeletions in patients with neurofibromatosis type 1 suggest that this chromosomal region is genetically unstable and prone to rearrangements.

Central Nervous System Neoplasms↗
PubMed2004

Genomic context of paralogous recombination hotspots mediating recurrent NF1 region microdeletion.

Recombination between paralogs that flank the NF1 gene at 17q11.2 typically results in a 1.5-Mb microdeletion that includes NF1 and at least 13 other genes. We show that the principal sequences responsible are two 51-kb blocks with 97.5% sequence identity (NF1REP-P1-51 and NF1REP-M-51). These blocks belong to a complex group of paralogs with three components on 17q11.2 and another on 19p13.13. Breakpoint sequencing of deleted chromosomes from multiple patients revealed two paralogous recombination hot spots within the 51-kb blocks. Lack of sequence similarity between these sites failed to suggest or corroborate any putative cis-acting recombinogenic motifs. However, the NF1 REPs showed relatively high alignment mismatch between recombining paralogs, and we note that the NF1REP hot spots were regions of good alignment bordered by relatively large alignment gaps. Statistical tests for gene conversion detected a single significant tract of perfect match between the NF1REPs that was 700 bp long and coincided with PRS2, the predominant recombination hot spot. Tracts of perfect match occurring by chance may contribute to breakpoint localization, but our result suggests that perfect tracts at recombination hot spots may be a result of gene conversion at sites at which preferential pairing occurs for other, as-yet-unknown reasons.

Base Sequence↗
PubMed2005

An integrated mBAND and submegabase resolution tiling set (SMRT) CGH array analysis of focal amplification, microdeletions, and ladder structures consistent with breakage-fusion-bridge cycle events in osteosarcoma.

Osteosarcoma (OS) is characterized by chromosomal instability and high-copy-number gene amplification. The breakage-fusion-bridge (BFB) cycle is a well-established mechanism of genomic instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. However, until now, there have been no high-resolution cytogenetic or genomic array studies of BFB events in OS. In the present study, multicolor banding (mBAND) FISH and submegabase resolution tiling set (SMRT) array comparative genomic hybridization (CGH) were used to identify and map genomic signatures of BFB events in four OS cell lines and one patient tumor. The expected intermediates associated with BFB-dicentric chromosomes, inverted duplications, and intra- and interchromosomal amplifications-were identified. mBAND analysis provided detailed mapping of rearrangements in 1p, 6p, and 8q and showed that translocation junctions were often in close proximity to fragile sites. More detailed mBAND studies of OS cell line MG-63 revealed ladderlike FISH signals of equally spaced interchromosomal coamplifications of 6p21, 8q24, and 9p21-p22 in a homogeneously staining region (hsr). Focal amplifications that concordantly mapped to the hsr were localized to discrete genomic intervals by SMRT array CGH. The complex amplicon structure in this hsr suggests focal amplifications immediately adjacent to microdeletions. Moreover, the genomic regions in which there was deletion/amplification had a preponderance of fragile sites. In summary, this study has provided further support for the role of the BFB mechanism and fragile sites in facilitating gene amplification and chromosomal rearrangement in OS.

Cell Line, Tumor↗
PubMedDate not supplied

Sex chromosome alignment at meiosis of azoospermic men with azoospermia factor microdeletion.

Deletions in the q arm of the Y chromosome result in spermatogenesis impairment. The aim of the present study was to observe the X and Y chromosome alignment in the spermatocytes of men with Y chromosome microdeletion of the azoospermia factor (AZF) region. This was performed by multicolor fluorescence in situ hybridization probes for the centromere and telomere regions. Testicular biopsies were performed in a testicular sperm extraction-intracytoplasmic sperm injection set-up in 11 azoospermic men: 8 (nonobstructive) with AZF deletions and 3 (obstructive) controls. Histological sections, cytology preparations of the testicular biopsies, and evaluation of the meiosis according to the percentage of XY and 18 bivalents formation were assessed. Spermatozoa were identified in at least one location in controls and specimens with AZFc-deleted Y chromosomes. Complete spermatocyte arrest was found in those with a deletion that included the entire AZFb region. Bivalent formation rate of chromosome 18 was high in all samples (81%-99%). In contrast, the rate of bivalent X-Y as determined by centromeric probes was lower but in the range favorable with spermatozoa findings in controls and patients with the AZFc deletion (56%-90%), but not in those with AZFb-c deletions (28%-29%). A dramatic impairment in the normal alignment of X and Y telomeres in the specimen with AZFb-c deletion was shown (29%), compared to the specimens with AZFc deletion (70%-94%). It is suggested that the absence of sperm cells in specimens with the entire AZFb and with AZFb-c deletions is accompanied by meiosis impairment, perhaps as a result of the extent of the deletion or because of the absence of genes that are involved in the X and Y chromosome alignment.

Biopsy↗
PubMed2001

Genomic organization, physical mapping, and involvement in Yq microdeletions of the VCY2 (BPY 2) gene.

VCY2 is a gene positioned within the AZFc locus of the Y chromosome, a region frequently deleted in infertile males. To investigate the involvement of this gene in idiopathic male infertility, we studied its genomic organization and localization. Analysis of the genomic structure demonstrated that the VCY2 gene is composed of 9 exons spanning 21 kb. FISH analysis on interphase nuclei with specific probes for exons 4-6, 7, and 8 demonstrated the presence of a single gene copy, and Fiber-FISH on relaxed chromatin indicated that VCY2 is located within the DAZ gene cluster. PCR, Southern blot, and FISH analysis on infertile patients with Yq microdeletions demonstrated the absence of VCY2 in all cases where deletions involved the DAZ gene, raising the question about the role of the VCY2 gene loss in the phenotype reported for DAZ-deleted patients.

Blotting, Southern↗