SEARCH · Search PubMed

Results for “Uniparental Disomy”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources

PubMedDate not supplied

Prader-Willi syndrome with an unusually large 15q deletion due to an unbalanced translocation t(4;15).

Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by deletions in the 15q11-q13 region, by maternal uniparental disomy of chromosome 15 or by imprinting defects. Structural rearrangements of chromosome 15 have been described in about 5% of the patients with typical or atypical PWS phenotype. An 8-year-old boy with a clinical diagnosis of PWS, severe neurodevelopmental delay, absence of speech and mental retardation was studied by cytogenetic and molecular techniques, and an unbalanced de novo karyotype 45,XY,der(4)t(4;15)(q35;q14),-15 was detected after GTG-banding. The patient was diagnosed by SNURF-SNRPN exon 1 methylation assay, and the extent of the deletions on chromosomes 4 and 15 was investigated by microsatellite analysis of markers located in 4qter and 15q13-q14 regions. The deletion of chromosome 4q was distal to D4S1652, and that of chromosome 15 was located between D15S1043 and D15S1010. Our patient's severely affected phenotype could be due to the extent of the deletion, larger than usually seen in PWS patients, although the unbalance of the derivative chromosome 4 cannot be ruled out as another possible cause. The breakpoint was located in the subtelomeric region, very close to the telomere, a region that has been described as having the lowest gene concentrations in the human genome.

Child↗

PubMed2005

Neurological aspects of the Angelman syndrome.

Angelman syndrome (AS) has emerged as an important neurogenetic syndrome due to its relatively high prevalence and easier confirmation of the diagnosis by improved genetic testing. In infancy, nonspecific clinical features of AS pose diagnostic challenges to the neurologist and these include any combination of microcephaly, seizure disorder, global developmental delay or an ataxic/hypotonic cerebral palsy-like picture. In later childhood, however, absent speech, excessively happy behavior, ataxia and jerky movements usually present as a recognizable clinical syndrome. Brain MRI shows nonspecific or normal findings but occasionally the characteristic EEG patterns alone can lead to the correct diagnosis. The physical, clinical and behavioral aspects appear to be attributable to localized CNS dysfunction of the ubiquitin ligase gene, UBE3A, located at 15q11.2. In certain brain regions, UBE3A normally has mono-allelic expression from the maternally derived chromosome 15. Several distinct genetic mechanisms can inactivate or disrupt the maternally derived UBE3A: chromosome microdeletions, paternal uniparental disomy, imprinting defects and intragenic UBE3A mutations. Those with the deletion type of AS are the most prevalent (about 70% of cases) and appear to have a more severe clinical phenotype. The unique epileptic patterns and distinct behavioral features may be related to multiple actions of UBE3A, possibly occurring during, as well as after, the time of neuronal development.

Adolescent↗

PubMed2006

High-resolution analysis of 9p loss in human cancer cells using single nucleotide polymorphism-based mapping arrays.

Single nucleotide polymorphism (SNP) mapping arrays were used to perform DNA copy number analysis of five human cancer cell lines (four malignant mesotheliomas; one non-small cell lung carcinoma) to identify and map the end-points of deletions of 9p. All five cell lines exhibited homozygous deletions encompassing the CDKN2A (alias INK4A/ARF) and CDKN2B loci. The DNA analysis profiles demarcated precisely two different, but overlapping, deletions in each mesothelioma cell line, but the lung cancer cells showed two copies of a single deletion. In the latter cell line, allele analysis revealed that virtually all SNPs for chromosome 9 were homozygous, suggestive of uniparental disomy. These findings demonstrate the utility of SNP-based mapping arrays for high-resolution analysis of genomic imbalances in cancer cells.

Cell Line, Tumor↗

PubMed2007

High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays.

Genomic copy number changes are detectable in many malignancies, including neuroblastoma, using techniques such as comparative genomic hybridization (CGH), microsatellite analysis, conventional karyotyping, and fluorescence in situ hybridization (FISH). We report the use of 10K single nucleotide polymorphism (SNP) microarrays to detect copy number changes and allelic imbalance in six neuroblastoma cell lines (IMR32, SHEP, NBL-S, SJNB-1, LS, and SKNBE2c). SNP data were generated using the GeneChip DNA Analysis and GeneChip chromosome copy number software (Affymetrix). SNP arrays confirmed the presence of all previously reported cytogenetic abnormalities in the cell lines, including chromosome 1p deletion, MYCN amplification, gain of 17q and 11q, and 14q deletions. In addition, the SNP arrays revealed several chromosome gains and losses not detected by CGH or karyotyping; these included gain of 8q21.1 approximately 24.3 and gain of chromosome 12 in IMR-32 cells; loss at 4p15.3 approximately 16.1 and loss at 16p12.3 approximately 13.2, 11q loss with loss of heterozygosity (LOH) at 11q14.3 approximately 23.3 in SJNB-1 cells; and loss at 8p21.2 approximately 23.3 and 9p21.3 approximately 22.1 with corresponding LOH in SHEP cells. The SNP arrays refined the mapping of the 2p amplicons in LS, BE2c, and IMR-32 cell lines, the 12q amplicon in LS cells, and also identified an 11q13 amplicon in LS cells. There was good concordance among SNP arrays, CGH, and karyotyping. SNP array analysis is a powerful tool for the detection of allelic imbalance in neuroblastoma and also allows identification of LOH without changes in copy number (uniparental disomy).

Allelic Imbalance↗

PubMed2006

Imprinting center analysis in Prader-Willi and Angelman syndrome patients with typical and atypical phenotypes.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic disorders caused by a deficiency of imprinted gene expression from the paternal or maternal chromosome 15, respectively. This deficiency is due to the deletion of the 15q11-q13 region, parental uniparental disomy of the chromosome 15, or imprinting defect (ID). Mutation of the UBE3A gene causes approximately 10% of AS cases. In this present study, we describe the molecular analysis and phenotypes of two PWS patients and four AS patients with ID. One of the PWS patients has a non-familial imprinting center (IC) deletion and displayed a severe phenotype with an atypical PWS appearance, hyperactivity and psychiatric vulnerability. The other PWS and AS patients did not present genetic abnormalities in the IC, suggesting an epimutation as the genetic cause. The methylation pattern of two AS patients showed a faint maternal band corresponding to a mosaic ID. One of these mosaic patients displayed a mild AS phenotype while the other displayed a PWS-like phenotype.

Adult↗

PubMed2004

A monozygotic twin pregnancy discordant for acardia and X-inactivation pattern.

Monochorionic, diamniotic twins discordant for acardia are reported. A 775 g acardius was dead, generally hydropic and severely malformed, while the other twin with a weight of 1314 g was phenotypically normal. Both twins had a normal 46 XX karyotype. Genotyping at 24 autosomal polymorphic loci revealed that the twins were identical (monozygotic) and ruled out uniparental disomy for chromosome 2. X-inactivation studies showed a skewed pattern in the acardiac twin and a normal random pattern in the co-twin, suggesting that the underdevelopment of the acardiac twin may have reflected the small number of original cells that were separated from the inner cell mass.

Abnormalities, Multiple↗

PubMed2005

Another patient with MECP2 mutation without classic Rett syndrome phenotype.

Rett syndrome and Angelman syndrome are two neurodevelopmental disorders characterized by partial overlapping features. Rett syndrome is frequently caused by a mutation in methyl-CpG-binding protein (MECP2) gene, localized on chromosome Xq28, whereas Angelman syndrome is frequently caused by different genetic anomalies at chromosome 15q11-q13 (deletions, uniparental disomy, imprinting center mutations, ubiquitin E3 ligase [UBE3A] gene mutations). Recently, some patients with a clinical diagnosis of Angelman syndrome were found to have a mutation in MECP2 gene. This report describes another patient with an Angelman-like phenotype and with an MECP2 mutation.

Angelman Syndrome↗

PubMed2006

Detailed analysis of the methylation patterns of the KvDMR1 imprinting control region of human chromosome 11.

The paternal repression of several genes in human chromosome 11p15.5 (mouse chromosome 7) is associated with paternal expression of a transcript called KCNQ1OT1 (also known as LIT1). This long transcript originates from a promoter that resides in a CpG island in intron 10 of the KCNQ1 gene and runs in an antisense orientation to the direction of the coding KCNQ1 transcript. The CpG island is maternally methylated but paternally nonmethylated. The CpG island loses its maternal methylation in over 50% of cases of Beckwith-Wiedemann syndrome who lack uniparental disomy. This loss is usually accompanied by biallelic expression of the KCNQ1OT1 transcript. We have examined the methylation status of this CpG island in somatic cell hybrids and diploid lymphoblasts using Southern hybridization and bisulfite sequencing techniques. We find that the maternal copy of the CpG island is methylated at all CpGs examined within the CpG island and uniformly paternally unmethylated. In addition, in BWS patients who have lost methylation of the CpG island, this loss occurs throughout the CpG island. Finally, we find that there is a switch in methylation patterns outside the CpG island from maternal methylation within the island to predominantly paternal methylation at sites flanking the CpG island.

Animals↗

PubMed1992

Nontraditional inheritance.

It has become clear in recent years that not all forms of inheritance follow classical mendelian laws regarding the equal contribution from both parents. These nontraditional modes of inheritance and gene expression include cytoplasmic inheritance, mosaicism, uniparental disomy, and genomic imprinting. All of these have been implicated in human genetic disorders and cancers and thus need to be kept in mind when trying to understand unusual observations in the clinic as well as when providing genetic counseling.

Chromosome Aberrations↗

PubMed1995

Mechanistic and developmental aspects of genetic imprinting in mammals.

Genetic imprinting in mammals allows the recognition and differential expression of maternal and paternal alleles of certain genes. Recent results from a number of laboratories indicate that, at least for some genes, gametic imprints, which must exist in order to mark chromosomes or genes as having been transmitted via sperm or ovum, are not by themselves sufficient to determine allele expression. Other postfertilization events are required, and these events are subject to both tissue-specific and developmental stage-specific regulation. Changes in imprinted gene methylation during preimplantation and fetal life indicate that the establishment of additional allele-specific modifications is likely to contribute to imprinted regulation. Disruptions in imprinting processes, loss of imprints, and loss of nonimprinted alleles through uniparental disomy are likely to contribute to a variety of developmental abnormalities and pathological conditions in both mice and humans.

Animals↗

PubMed2006

Prader-Willi syndrome: atypical psychoses and motor dysfunctions.

Prader-Willi syndrome (PWS) is the result of a lack of expression of genes on the paternally derived chromosome 15q11-q13 and can be considered as a hypothalamic disorder. Its behavioral phenotype is characterized by ritualistic, stereotyped, and compulsive behaviors as well as motor abnormalities. After adolescence, recurrent affective psychoses are relatively frequent, especially in patients with uniparental disomy. These psychotic states have a subacute onset with complete recovery and comprise an increase of psychomotor symptoms that show resemblance with catatonia. Some evidence has emerged that gamma-aminobutyric acid (GABA) dysfunctionality is involved in both PWS and catatonia. Treatment of these atypical psychoses should preferably include GABA mimetic compounds like lorazepam, valproic acid, and possibly topiramate.

Adolescent↗

PubMed1996

Diagnostic test for the Prader-Willi syndrome by SNRPN expression in blood.

BACKGROUND: Prader-Willi syndrome (PWS) is caused by alterations of the paternally derived chromosome 15 or by maternal uniparental disomy. The gene for the small nuclear ribonucleoprotein polypeptide N (SNRPN) is expressed only from the paternally derived chromosome 15, due to epigenetic imprinting. The SNRPN gene is not expressed in any patients with PWS regardless of the underlying cytogenetic or molecular causes. METHODS: To develop a rapid molecular diagnostic assay for PWS, we tested the expression of the SNRPN gene and a control gene in 9 patients with PWS and 40 control individuals by PCR analysis of reverse transcribed mRNA from blood leucocytes. We then tested 11 blood samples from patients with suspected PWS. FINDINGS: SNRPN expression could readily be detected in blood leucocytes by PCR analysis in all control samples but not in samples from known PWS patients. Four suspected plus were negative for SNRPN expression were found to have chromosome 15 rearrangements, while the diagnosis of PWS was excluded in the remaining seven with normal SNRPN expression based on clinical, molecular, and cytogenetic findings. INTERPRETATION: The SNRPN-expression test is rapid and reliable in the molecular diagnosis of Prader-Willi syndrome.

Autoantigens↗

PubMed1999

Hemizygous deletions of chromosome band 16q24 in Wilms tumor: detection by fluorescence in situ hybridization.

Loss of heterozygosity (LOH) for markers on chromosome arm 16q in Wilms tumor has been linked to an increased risk of treatment failure. We therefore postulated that fluorescence in situ hybridization (FISH) with probes from this region might enhance current strategies for identifying high-risk patients at diagnosis. In a blinded comparative pilot study of 19 Wilms tumor samples from 18 patients with favorable histology, FISH and DNA polymorphism analysis yielded concordant results in 14 cases, either retention (n = 6) or loss (n = 8) of chromosome arm 16q markers. Discordant findings in 4 of the 5 remaining cases resulted from detection of LOH, but no loss by FISH. Two of these cases, directly comparable at marker D16S422, appeared to have tumor-specific uniparental disomy, in that 2 copies of D16S422 and the 16 centromere were evident, despite LOH. In 2 other cases, the discrepancies could be explained by LOH confined to loci distal to the D16S422 locus. In the fifth case, FISH detected 2 distinct populations of tumor cells, one characterized by normal diploidy and the other by monosomy 16, whereas DNA polymorphism analysis failed to indicate LOH altogether. Thus, FISH confirmed the presence of allelic loss (hence, the possible location of biologically important tumor suppressor genes) on the distal long arm of chromosome 16 in cases of favorable-histology Wilms tumor, with the advantages of technical simplicity, successful analysis of samples that were otherwise uninformative by analysis of DNA polymorphisms, and the addition of internal controls for chromosomal aneusomy. We suggest that combined analysis of the chromosome 16q region in Wilms tumor by FISH and DNA polymorphism analysis would improve evaluations to identify high-risk patients who might benefit from alternative therapy.

Child↗

PubMed1999

Angelman syndrome: a review of clinical and genetic aspects.

This paper reviews Angelman syndrome (AS) with regard to the clinical features in childhood and adulthood, epileptic seizures and EEG findings, neuroimaging studies and the present knowledge on the genetic mechanisms underlying this syndrome. Different clinical phenotypes and genotypes of AS are described, including chromosome 15q11-13 deletion, uniparental disomy, methylation imprinting abnormalities and mutations in the UBE3A gene.

Angelman Syndrome↗

PubMed1997

Chorionic villus sampling.

Chorionic villus sampling (CVS) has been used a successful and safe first-trimester prenatal diagnostic technique for over 12 years. Developed to avoid the medical and psychological complications of later prenatal diagnosis by amniocentesis, CVS rapidly has become a primary tool for the diagnosis of fetal cytogenetic, molecular, and biochemical disorders. In addition, its development has led to an improved understanding of several biological processes, including confined placental mosaicism and uniparental disomy.

Chorionic Villi Sampling↗

PubMed2000

Delta-like and gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12.

The distal portion of mouse chromosome 12 is imprinted. To date, however, Gtl2 is the only imprinted gene identified on chromosome 12. Gtl2 encodes multiple alternatively spliced transcripts with no apparent open reading frame. Using conceptuses with maternal or paternal uniparental disomy for chromosome 12 (UPD12), we found that Gtl2 is expressed from the maternal allele and methylated at the 5' end of the silent paternal allele. A reciprocally imprinted gene, Delta-like (Dlk), with homology to genes involved in the Notch signalling pathway was identified 80kb upstream of Gtl2. Dlk was expressed exclusively from the paternal allele in both the embryo and placenta, but the CpG-island promoter of Dlk was completely unmethylated on both parental alleles. Rather, a paternally methylated region was identified in the last exon of the active Dlk allele. The proximity, reciprocal imprinting and methylation in this domain are reminiscent of the co-ordinately regulated Igf2-H19 imprinted domain on mouse chromosome 7. Like H19 and Igf2, Gtl2 and Dlk were found to be co-expressed in the same tissues throughout development, though not after birth. These results have implications for the regulation, function and evolution of imprinted domains.

Alleles↗

PubMed2002

Genomic imprinting contributes to thyroid hormone metabolism in the mouse embryo.

Many genes subject to genomic imprinting function in a number of endocrine/paracrine pathways that are important for normal mammalian development. Here, we show that an endocrine/paracrine pathway involving thyroid hormone metabolism is also regulated by imprinting. Thyroid hormone action depends on thyroid hormone receptors and their predominant ligand, 3,5,3'-triiodothyronine (T3). In vivo, thyroid hormone levels are maintained within the physiological range through the interaction of three iodothyronine deiodinases, D1, D2, and D3. D3 inactivates thyroxine (T4) and T3 by 5-deiodination, and the gene for this enzyme, Dio3, lies in the imprinted domain on human chromosome 14q32/distal mouse chromosome 12. Here, we report the imprinting of Dio3, which is expressed preferentially from the paternal allele. No differentially methylated region was identified in the CpG-island promoter, which is completely unmethylated. Localization of transcripts suggests that Dio3 may be exerting its function in both endocrine and autocrine/paracrine manners. An assay was developed for T3, and we show that its levels in maternal and paternal uniparental disomy (UPD) 12 fetuses are reciprocally affected. These results demonstrate that disruption of the imprinting status of Dio3 results in abnormal thyroid hormone levels and may contribute to the phenotypic abnormalities in UPD12 mice and UPD14 humans.

Animals↗

PubMed2000

Adult patients with Prader-Willi syndrome: clinical characteristics, life circumstances and growth hormone secretion.

Prader-Willi syndrome is characterized by a typical clinical phenotype and by a complex genetic basis that includes large deletions, uniparental disomy and imprinting mutations of chromosome region 15q11-q13. This report delineates the clinical characteristics, morbidity and growth hormone secretory status of 19 adults with Prader-Willi syndrome. The patients were 18-34 years of age. Morbidity included marked obesity with body mass index in excess of 30 kg/m2 (grade 1-3 according to WHO), metabolic diseases, sleep apnoea and lipolymphoedema. Severe growth hormone deficiency (GHD) was seen in 38% of the patients, and levels of insulin-like growth factor I were decreased in 87%. Thus, GHD is seen, not only in children with Prader-Willi syndrome, but also in adults with the syndrome.

Adolescent↗