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At least 19 recordsLinked to original sources

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↗

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↗

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↗

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↗

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↗

PubMed1994

A systematic search for uniparental disomy in carriers of chromosome translocations.

A systematic search was made for uniparental disomy in carriers of apparently balanced chromosome translocations who also had unexplained abnormalities of mental or physical development. Of 65 families studied, biparental origin of both translocated chromosomes was demonstrated in 64, and only 1 case of maternal uniparental disomy of chromosome 14 was detected in the carrier of a Robertsonian t(13q14q). We conclude that uniparental disomy is a rare occurrence in this population.

Chromosome Aberrations↗

PubMed2026

UPDhmm: detecting uniparental disomy from NGS trio data.

SUMMARY: Uniparental disomies (UPDs) are copy-neutral chromosomal alterations that occur when both copies of a chromosome pair (entire or segmental) come from one parent. UPDs, including isodisomies (identical parental chromosome) and heterodisomies (two different homologs from the same parent), reflect meiotic and/or mitotic aberrations of chromosomal segregation that can be associated with congenital or acquired disease. Despite their relevance, current methods to detect UPDs using sequence data (exomes or genomes) have limited sensitivity for small events, cannot precisely determine the UPD sub-type or coordinates, and perform poorly when including individuals or populations with consanguinity. We present UPDhmm, a novel tool that uses trio-based sequence data (proband and parents) and models inheritance patterns. UPDhmm predicts the most likely inheritance scenario, normal Mendelian inheritance versus UPD event, based on genotype combinations using a Hidden Markov Model (HMM). We validated the method using simulations on exome and genome data from 1000-Genomes projects. UPDhmm overperformed currently available methods in detecting simulated UPD events in both data types. We applied UPDhmm to a collection of nearly 2400 families with a proband with autism spectrum disorder (Simons Simplex Collection Project) and identified UPD events in two affected individuals, one of them previously unreported. These two events, a paternal isodisomy of chr8 and a maternal heterodisomy of chr22, can be genetic causes of the disease, demonstrating the clinical utility of UPDhmm. Thus, UPDhmm can facilitate the incorporation of UPD detection into clinical pipelines of genomic analysis. AVAILABILITY AND IMPLEMENTATION: UPDhmm is implemented in R and is available in the Bioconductor package (version 1.5.0): https://www.bioconductor.org/packages/release/bioc/html/UPDhmm.html. The source code can be found at https://github.com/martasevilla/UPDhmm under the MIT license.

Uniparental Disomy↗

PubMed2000

Mechanisms leading to uniparental disomy and their clinical consequences.

Uniparental disomy (UPD) refers to the situation in which both copies of a chromosome pair have originated from one parent. In humans, it can result in clinical conditions by producing either homozygosity for recessive mutations or aberrant patterns of imprinting. Furthermore, UPD is frequently found in conjunction with mosaicism for a chromosomally abnormal cell line, which can also contribute to phenotypic abnormalities. Investigations into the mechanisms by which UPD may arise have helped to expand our general awareness of the impact of chromosomal abnormalities and chromosomal mosaicism in normal human development. Specifically, it appears that errors in the transmission of a chromosome from parent to gamete and during early somatic cell divisions are remarkably common but that embryo and cell selection during early embryogenesis help to ensure the presence of a numerically balanced chromosome complement in the developing fetus. UPD is also likely to occur within a portion of cells in all individuals simply as a consequence of somatic recombination occurring during mitotic cell divisions. This can be an important step in cancer development as well as a contributing factor to other late onset diseases. This review summarizes mechanisms by which UPD may arise and their associated clinical consequences.

Animals↗

PubMed2000

Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15.

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in approximately 2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader-Willi syndrome patients. Such a difference cannot be easily accounted for if 'gamete complementation' is the main mechanism leading to UPD. If we assume that non-disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post-zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non-random X-chromosome inactivation (XCI) observed in maternal UPD15 patients (p < 0.001) provides indirect evidence that a post-zygotic error is also typically involved in loss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as compared with normal controls. This may be simply the consequence of an age association with maternal non-disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.

Adult↗

PubMed2000

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Aneuploidy↗

PubMed1998

Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus.

Transient neonatal diabetes mellitus occurs in growth-retarded infants, has an incidence of 1 in 400000 live births and has been associated with both paternal uniparental disomy of chromosome 6 and paternal duplications of 6q. We analysed samples from our cohort of patients with transient neonatal diabetes mellitus for uniparental disomy of chromosome 6 using polymorphic microsatellite repeat analysis. We report here the fifth case of paternal uniparental disomy of chromosome 6 associated with classic transient neonatal diabetes mellitus and estimate that uniparental disomy of chromosome 6 accounts for approximately one fifth of cases of transient neonatal diabetes mellitus.

Chromosomes, Human, Pair 6↗

PubMed1999

Maladaptive behavior differences in Prader-Willi syndrome due to paternal deletion versus maternal uniparental disomy.

Maladaptive behavior was compared across 23 people with Prader-Willi syndrome due to paternal deletion to 23 age- and gender-matched subjects with maternal uniparental disomy. Controlling for the higher IQs of the uniparental disomy group, deleted cases showed significantly higher maladaptive ratings on the Child Behavior Checklist's Internalizing, Externalizing, and Total domains as well as more symptom-related distress on the Yale-Brown Obsessive-Compulsive Scale. Across both measures, deleted cases were more apt to skin-pick, bite their nails, hoard, overeat, sulk, and withdraw. A dampening of symptom severity is suggested in Prader-Willi syndrome cases due to maternal uniparental disomy. Findings are compared to Angelman syndrome, and possible genetic mechanisms are discussed, as are implications for Prader-Willi syndrome and obsessive-compulsive behaviors.

Adolescent↗