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At least 19 recordsLinked to original sources
PubMed2003

Skeletal defects in paternal uniparental disomy for chromosome 14 are re-capitulated in the mouse model (paternal uniparental disomy 12).

Human paternal uniparental disomy for chromosome 14 (upd(14)pat) presents with skeletal abnormalities, joint contractures, dysmorphic facial features and developmental delay/mental retardation. Distal human chromosome 14 (HSA14) is homologous to distal mouse chromosome 12 (MMU12) and both regions have been shown to contain imprinted genes. In humans, consistent radiographic findings include a narrow, bell-shaped thorax with caudal bowing of the anterior ribs, cranial bowing of the posterior ribs and flaring of the iliac wings without shortening or dysplasia of the long bones. Mice with upd(12)pat have thin ribs with delayed ossification of the sternum, skull and feet. In both mice and humans, the axial skeleton is predominantly affected. We hypothesize that there is an imprinted gene or genes on HSA14/MMU12 that specifically affects rib/thorax development and the maturation of ossification centers in the sternum, feet and skull with little effect on long bone development.

Animals↗
PubMed2000

Multipoint genetic mapping with uniparental disomy data.

Uniparental disomy (UPD) refers to the presence of two copies of a chromosome from one parent and none from the other parent. In genetic studies of UPDs, many genetic markers are usually used to identify the stage of nondisjunction that leads to UPD and to uncover the associated unusual patterns of recombinations. However, genetic information in such data has not been fully utilized because of the limitations of the existing statistical methods for UPD data. In the present article, we develop a multilocus statistical approach that has the advantages of being able to simultaneously consider all genetic markers for all individuals in the same analysis and to allow general models for the crossover process to incorporate crossover interference. In particular, for a general crossover-process model that assumes only that there exists in each interval at most one crossover, we describe how to use the expectation-maximization algorithm to examine the probability distribution of the recombination events underlying meioses leading to UPD. We can also use this flexible approach to create genetic maps based on UPD data and to inspect recombination differences between meioses exhibiting UPD and normal meioses. The proposed method has been implemented in a computer program, and we illustrate the proposed approach through its application to a set of UPD15 data.

Algorithms↗
PubMed1996

Silver-Russell syndrome and exclusion of uniparental disomy.

Recently, maternal uniparental disomy for the entire chromosome 7 was described in three of 25 Silver-Russell syndrome sporadic cases, yet the etiology of the remaining cases is unclear. Two cases with Silver-Russell syndrome and a balanced translocation involving the 17q25 had been reported. We looked for evidence of genomic imprinting due to uniparental disomy 17 in seven patients with sporadic Silver-Russell syndrome and their parents. Additionally, chromosomes 7, 8, 11 and 20 were studied. Uniparental disomy was ruled out for all these chromosomes in six of seven families; one family was informative only for chromosome 17. Not-withstanding our negative results, it is still possible that uniparental disomy plays a part in this syndrome. A mutation in a Mendelian gene in 17q25 could also account for the Silver-Russell syndrome etiology.

Abnormalities, Multiple↗
PubMed2005

Long-acting gonadotropin-releasing hormone analogue treatment for central precocious puberty in maternal uniparental disomy chromosome 14.

Uniparental disomy (UPD) is the inheritance of a chromosome pair from one parent and is increasingly recognized as a cause of abnormal phenotypes either due to imprinted genes or, in the case of isodisomy, to homozygosity of recessive alleles. Maternal uniparental disomy for chromosome 14 (matUPD[14]) may cause a characteristic phenotype including precocious puberty. Central precocious puberty (CPP) was diagnosed in a 6-year-old girl with some dysmorphic features, truncal obesity, small hands, and small feet. Cytogenetic analysis of her peripheral blood demonstrated chromosomal rearrangement: Robertsonian translocation 45, XX, der(13;14)(q10;q10). MatUPD(14) was demonstrated in the patient by haplotype analysis of chromosome 14, showing that the CPP is one of the features caused by matUPD(14). The CPP was successfully treated with higher dosage of long-acting gonadotropin releasing hormone (GnRH) analogue, Leuprolide, 90 microg/kg/month. This is the first report that describes GnRH analogue treatment for CPP associated with matUPD(14), suggesting that the GnRH analogue treatment is appropriate even for such a specific type of CPP.

Body Height↗
PubMed1999

Investigation of two cases of paternal disomy 13 suggests timing of isochromosome formation and mechanisms leading to uniparental disomy.

Uniparental disomy (UPD) is the abnormal inheritance of two copies of a chromosome from the same parent. Possible mechanisms for UPD include trisomy rescue, monosomy rescue, gametic complementation, and somatic recombination. Most of these mechanisms can involve rearranged chromosomes, particularly isochromosomes and Robertsonian translocations. Both maternal and paternal UPD have been reported for most of the acrocentric chromosomes. However, only UPD for chromosomes 14 and 15 show an apparent imprinting effect. Herein, we present two cases of paternal UPD 13 involving isochromosomes. Both cases were referred for UPD studies due to the formation of a de novo rea(13q13q). Case 2 was complicated by the segregation of a familial rob(13q14q) of maternal origin. Both propositi were phenotypically normal at the time of examination. Polymorphic marker analysis in Case 1 showed the distribution of alleles of markers along chromosome 13 to be complete isodisomy, consistent with an isochromosome. This rearrangement could have occurred either meiotically, without recombination, or mitotically. A likely mechanism for UPD in this case is monosomy rescue, through postzygotic formation of the isochromosome. In Case 2 the distribution of proximal alleles indicated an isochromosome, but recombination was evident. Thus, this isochromosome must have formed prior to or during meiosis I. A likely mechanism for UPD in this case is gametic complementation, since the mother carries a rob(13q14q) and is at risk of producing aneuploid gametes. However, trisomy rescue of a trisomy 13 conceptus cannot be completely excluded. Given that both cases were phenotypically normal, these data further support that paternal UPD 13 does not have an adverse phenotypic outcome and, thus, does not show an apparent imprinting effect.

Alleles↗
PubMed2005

A rapid microarray based whole genome analysis for detection of uniparental disomy.

To date, uniparental disomy (UPD) with phenotypic relevance is described for different chromosomes and it is likely that additional as yet unidentified UPD phenotypes exist. Due to technical difficulties and limitations of time and resources, molecular analyses for UPD using microsatellite markers are only performed in cases with specific phenotypic features. In this study, we carried out a whole genome UPD screening based on a microarray genotyping technique. Six patients with the diagnosis of both complete or segmental UPD including Prader-Willi syndrome (PWS; matUPD15), Angelman syndrome (AS; patUPD15), Silver-Russell syndrome (SRS; matUPD7), Beckwith-Wiedemann syndrome (BWS; patUPD11p), pseudohypoparathyroidism (PHP; patUPD20q) and a rare chromosomal rearrangement (patUPD2p, matUPD2q), were genotyped using the GeneChip Human Mapping 10K Array. Our results demonstrate the presence of UPD in the patients with high efficiency and reveal clues about the mechanisms of UPD formation. We thus conclude that array based SNP genotyping is a fast, cost-effective, and reliable approach for whole genome UPD screening.

Angelman Syndrome↗
PubMed1994

A test for uniparental disomy in Saccharomyces cerevisiae.

Uniparental disomy is a condition in a diploid organisms where one parental chromosome is absent and its homolog from the other parent duplicated. It can be a cause of genetic somatic disease in mammals because of imprinting. Imprinting creates a sex-specific pattern of epigenetic gene inactivation at least in mammals and, consequently, a complete set of both maternal and paternal chromosomes is required for normal development. Moreover, it has been shown for several types of tumors that recessive tumor alleles originally present in a heterozygous condition in normal somatic tissue have become homozygous in the tumor cells. Homozygosity is frequently caused by uniparental disomy. A similar situation is found in Saccharomyces cerevisiae where the spontaneous or induced expression of linked recessive alleles flanking a common centromere is preponderantly due to isodisomy where one of the homologs is lost and the retained homolog duplicated. In contrast to the situation in Aspergillus nidulans, isodisomy does not appear to be caused by two sequential and independent events of malsegregation resulting first in an unstable trisomic condition from which a normal disomic condition is restored through segregational loss of one supernumerary chromosome. Rather, an as yet unknown mechanism seems to directly generate isodisomy and thus Saccharomyces cerevisiae could provide a short-term test for the detection of this type of genetic change.

Chromosome Deletion↗
PubMed2005

Maternal uniparental disomy chromosome 14: case report and literature review.

Uniparental disomy is a genetic cause of disease implicated in a wide variety of neurologic disorders. A recently identified condition is maternal uniparental disomy for chromosome 14 (mUPD14) syndrome. A child with hypotonia and developmental delay was found to have mUPD14 after identification of a balanced karyotypic rearrangement involving both chromosomes 14. We explore the genetic mechanisms by which uniparental disomy can cause clinical abnormalities and karyotypic findings that should raise suspicion for uniparental disomy, review the literature on the mUPD14, and discuss clinical indications on which to suspect this diagnosis. Although it is more difficult to establish a diagnosis in the absence of visible karyotypic abnormalities involving chromosome 14, a distinct phenotype exists in mUPD14 syndrome: in utero growth restriction, congenital hypotonia, gross motor delay, arrested hydrocephalus, mild to moderate mental retardation, joint hyperextensibility, short stature, and precocious puberty. Testing for mUPD14 should be considered in infants with generalized hypotonia who have a history of in utero growth restriction.

Chromosomes, Human, Pair 14↗
PubMed2003

A multiplex methylation PCR assay for identification of uniparental disomy of chromosome 7.

Uniparental disomy of chromosome 7 (UPD7) is associated with abnormal phenotypic effects because of inappropriate expression of imprinted genes on chromosome 7. Based on the differential methylation of the promoter region of the imprinted PEG1/MEST locus at 7q32, we designed a multiplex methylation PCR (mPCR) assay to rapidly distinguish UPD7 from biparental inheritance of chromosome 7. Primers were designed to produce different sized PCR amplicons based on the parent of origin-specific methylation at this locus; electrophoresis of PCR amplicons showed a 189-bp product from the methylated maternal allele and a 109-bp product from the unmethylated paternal allele. This mPCR assay correctly predicted the chromosome 7 imprinting status in normal control and UPD7 samples. Previous assays for UPD7 required genotyping of the proband and parents, or separate maternal- and paternal-specific mPCR reactions. The advantage of this assay is that parental samples are not required and that amplification of both alleles in the same reaction is simpler and provides an internal control. This multiplex mPCR assay will be useful in screening for UPD7 in patients with Silver-Russell syndrome (SRS; also Russell-Sliver syndrome, RSS), primordial growth retardation, and in patients with supernumerary marker chromosomes or chromosome rearrangements of chromosome 7 origin.

Alleles↗
PubMed1993

Genetic syndromes and uniparental disomy: a study of 16 cases of Brachmann-de Lange syndrome.

Uniparental disomy is responsible for a proportion of cases in Prader-Willi, Angelman, and Wiedemann-Beckwith syndromes. In these syndromes, the chromosomes involved are thought to contain one or more imprinted genes. When two copies of the imprinted (inactivated) gene are inherited from a single parent through uniparental disomy or the active gene is deleted, the phenotype of the syndrome results. Our goal is to identify additional syndromes caused by uniparental disomy. Our approach is to select syndromes that appear to have more than one mode of inheritance and are occasionally associated with a cytogenetic abnormality. Given this criterion, we have chosen Brachmann-de Lange Syndrome (BDLS) to investigate since the phenotype is similar to that found in patients with dup(3q). We have studied 16 probands with BDLS and their parents using a multiplex of four PCR-based polymorphic loci on chromosome 3. None of the probands studied had uniparental disomy for chromosome 3 and all demonstrated normal biparental inheritance for at least one locus. Given these results, uniparental disomy of chromosome 3 does not appear to be a major contributor to the syndrome. Additionally, both maternally and paternally derived chromosome abnormalities have resulted in the dup(3q) phenotype and dominant inheritance of BDLS from both mildly affected mothers and fathers have been reported which suggests that imprinting is not involved in these syndromes.

Chromosomes, Human, Pair 3↗
PubMed1991

Uniparental disomy, isodisomy, and imprinting: probable effects in man and strategies for their detection.

The concept of uniparental disomy--the presence of a chromosome pair derived solely from one parent in a diploid offspring--was introduced in 1980 as a probable consequence of the high rate of germ cell aneuploidy in man, and has now been convincingly demonstrated through molecular analyses in several families. A most likely mechanism for the production of uniparental disomy is the chance reunion, and complementation, of 2 gametes aneuploid for the same chromosome member; uniparental disomy could also occur through other mechanisms including postzygotic non-segregation in a trisomic conceptus. Uniparental disomy may result in isodisomy, i.e., homozygosity of a series of contiguous alleles in a pair of homologues. The presence and degree of isodisomy in an offspring depend in turn on the occurrence, timing, and extent of the meiotic recombination that had occurred in the chromosome pair of the disomic gamete involved. Uniparental disomy with or without isodisomy can explain a number of unusual observations, such as the unexpected pattern of transmission of a genetic disorder. The two may be associated with an imprinting effect to produce pathological phenotypes, as has been observed in the mouse, and may be the basis for a number of syndromes of as yet unclear cause. The evidence for uniparental disomy, isodisomy, and imprinting in man is reviewed, and strategies for their detection presented.

Chromosome Aberrations↗
PubMed2001

[Uniparental disomy 7 in the pathogenesis of Silver-Russell syndrome].

The authors report the frequency and the clinical signs of uniparental disomy of chromosome 7 in Silver-Russell syndrome patients. A cohort of 73 families were typed with Short Tandem Repeat markers from chromosomes 7. In 6 patients maternal uniparental disomy 7 (UPD7) was detected. Summarising their data and those from the literature, an overall frequency of maternal uniparental disomy 7 of approximately 10% can be estimated. Allelic distribution in two of their maternal uniparental disomy 7 families indicates complete isodisomy whereas allelic patterns in the other four families are consistent with partial and complete heterodisomy, respectively. The clinical features of maternal uniparental disomy 7 patients do not show any deviation from the non-uniparental disomy 7 patients. Additionally, there was not hint for possible influences of iso- or heterodisomy, possibly associated with different stages of mosaicism. Their results demonstrate the necessity to screen SRS patients for UPD7 although the effect of UPD7 cannot be correlated to the SRS phenotype yet. Furthermore, an association between UPD for chromosomes other than 7 and SRS seems to be negligible. Vice versa, maternal UPD7 is not detectable in non-SRS patients. Therefore, testing for maternal UPD7 can be restricted to SRS families, searching for other UPDs in this population does not seem to be reasonable. Additionally, cytogenetic analysis should also be performed in SRS patients: identification of commonly involved chromosomal regions should allow narrowing down a SRS-relevant region.

Abnormalities, Multiple↗
PubMed2005

Differences in behavioural phenotype between parental deletion and maternal uniparental disomy in Prader-Willi syndrome: an ERP study.

OBJECTIVE: Paternal deletion and maternal uniparental disomy are the principal genetic subtypes associated with Prader-Willi syndrome (PWS). Recent clinical findings suggest differences in phenotype between these subtypes. The present experimental study addresses this issue using a cognitive psycho-physiological setup. METHODS: Behaviour and event-related brain activity (ERP) was recorded by a continuous performance response inhibition task (CPT-AX) in adults with paternal deletion PWS (n=11), maternal uniparental disomy PWS (n=11) and normal controls (n=11). The dependent behavioural variables of the CPT-AX task were reaction time and correct scores. For the ERPs the N200 and P300 components were included which are related to early modality-specific inhibition and late general inhibition, respectively. RESULTS: The disomy group had fewer correct scores and increased reaction times as compared to the CPT-AX task than the control and deletion group. Both PWS subgroups differed significantly from the control group for the N200 amplitude. Only the control group showed the typical task modulation for the N200 amplitude. The amplitude of the P300 component was considerably smaller in the uniparental disomy group than in the deletion and control groups. CONCLUSIONS: The ERP results suggest that early modality specific inhibition is impaired in both PWS genetic subtypes. Late general inhibition is impaired in the uniparental disomy group only. Thus, although the ERP data suggests a common impairment in early visual inhibition processing, uniparental disomy and parental deletion genetic PWS subtypes clearly differ in their behavioural and brain activation phenotypes. SIGNIFICANCE: The present study is the first experimental demonstration which explains the two principal genetic mechanisms that hinder the expression of the genes at 15q11-q13g in PWS result in different behavioural phenotype.

Adult↗
PubMedDate not supplied

[Evaluation of the role of uniparental disomy in early embryolethality of man].

We carried out systematic studies of the contribution of uniparental disomy for eight human chromosomes, 2, 9, 11, 15, 16, 19, 20, and 21, to the etiology of spontaneous mortality of human embryos. Most of these chromosomes have regions with orthologous imprinted genes syntenic with those on mouse chromosomes, the disturbed expression of which is related to embryolethality in mice. Screening of uniparental disomy in spontaneous 5- to 16-week abortuses was performed by evaluation of the pattern of inheritance of alleles of polymorphic microsatellite loci located in the studied chromosomes. A total of 100 human embryos with cytogenetically determined normal karyotype were studied, in which arrest at the early stages of intrauterine development was determined by ultrasound examination of pregnant women. During this study, 13 embryos were discarded due to karyotype anomalies or nonpaternity. No cases of uniparental disomy were found among the 87 studied abortuses for any of chromosomes studied. The analysis of the results of this study and four other studies concerning the search for uniparental disomy in dead embryos and fetuses did not reveal its elevated frequency in spontaneous abortuses as compared to the theoretically expected value based on evaluation of the probable combination of meiotic errors in human gametes. The data we obtained suggest that, first, uniparental disomies for human chromosomes that have regions with orthologous imprinted genes syntenic with mouse chromosomes do not contribute noticeably to the death of human embryos at the early developmental stages and, second, the mechanisms underlying embryolethality as a result of disturbed expression of imprinted loci differ markedly in mammals evolutionarily remote from one other.

Abortion, Spontaneous↗
PubMed1997

The incidence of uniparental disomy associated with intrauterine growth retardation in a cohort of thirty-five severely affected babies.

OBJECTIVE: Our purpose was to screen for uniparental disomy 35 babies with idiopathic intrauterine growth retardation < 5th percentile. STUDY DESIGN: The placenta and the baby's blood were conventionally karyotyped. Deoxyribonucleic acid from the parents, the baby's blood, and the placenta were then screened for uniparental disomy for 12 candidate chromosomes with use of chromosome-specific polymorphic deoxyribonucleic acid markers. RESULTS: Two cases of maternal uniparental disomy for chromosome 16 were found associated with confined placental mosaicism for chromosome 16. No other uniparental disomy was found for any of the 12 chromosomes tested. Four structural chromosome abnormalities were also found in this cohort through standard karyotyping. CONCLUSION: Uniparental disomy for the chromosomes tested does not explain the etiology of the majority of cases of intrauterine growth retardation < 5th percentile. Maternal uniparental disomy for chromosome 16 accounts for 5% of this cohort. Structural chromosomal abnormalities are also much higher than expected at 11%.

Chromosome Aberrations↗
PubMed2000

No evidence for uniparental disomy of the sex chromosomes in idiopathic male infertility.

Uniparental disomy (UPD) is a rare genetic aberration characterized by the uni- rather than biparental inheritance of a pair of homologous chromosomes. Among the various adverse clinical effects that UPD can have in humans, abnormalities of the male reproductive system have been described in UPD of the chromosomes 7, 11, 14 and 15. Given the considerable rate of sex chromosomal aneuploidy in human gametes and zygotes, we postulated that paternal uniparental disomy of the sex chromosomes might be a cause of otherwise unexplained male infertility. With a set of highly polymorphic DNA markers the parental origin of the X chromosome in 41 men with severe idiopathic infertility was determined. In all patients the X chromosome was derived from the mother, indicating regular biparental inheritance of the sex chromosomes. We thus obtained no evidence that paternal uniparental disomy of the X and Y chromosomes is a mechanism underlying idiopathic male infertility.

Chromosome Aberrations↗
PubMed2001

Statistical analysis of uniparental disomy data using hidden Markov models.

Genetic studies of uniparental disomy (UPD) employing many markers have helped geneticists to gain a better understanding of the molecular mechanisms underlying nondisjunction. However, most existing methods cannot simultaneously analyze all genetic markers and consistently incorporate crossover interference; they thus fail to make the most use of genetic information in the data. In the present article, we describe a hidden Markov model for multilocus uniparental disomy data. This method is based on the chi-square model for the crossover process and can simultaneously incorporate all marker information including untyped and uninformative markers. We then apply this novel method to analyze a set of UPD15 data.

Biometry↗