Complex and segmental uniparental disomy updated

Kotzot, Dieter

doi:10.1136/jmg.2008.058016

Cited by 115 publications

(122 citation statements)

References 146 publications

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“…Moreover, smaller UPD events are less likely to be pathogenic and are much more likely to be mosaic (Kotzot 2008), implying that alternative UPD detection approaches, based on B-allele frequency of proband genotypes, would be more appropriate for segmental UPD events. We implemented UPD detection on 1057 unique trios and identified four probands with whole-chromosomal isodisomy, one with whole-chromosomal heterodisomy, and one proband with segmental uniparental isodisomy of 10 Mb.…”

Section: à323mentioning

confidence: 99%

“…The UPD chromosome can be characterized in four ways: (1) extent: affecting the whole chromosome (complete) or a portion of the chromosome (segmental); (2) zygosity: affecting all cells (constitutive) or a proportion of cells (mosaic); (3) by homolog segregation: whether the centromeric regions are identical (isodisomy) or represent both grandparental homologs (heterodisomy); and (4) by parental-origin: maternal or paternal. The origin of UPD often entails meiotic nondisjunction followed by a mitotic rescue event, but the possibility of crossing-over of homologs and missegregation of translocated chromosomes and other complex events are possible (Kotzot 2008).…”

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confidence: 99%

“…UPD has three important disease associations: first, by disrupting the inheritance of essential parent-specific epigenetic modifications, causing imprinting disorders (Yamazawa et al 2010); second, by converting deleterious alleles bequeathed from a heterozygous parent to a homozygous state, causing recessive disease (Zlotogora 2004); and third, by its relationship to incomplete trisomy rescue, resulting in residual trisomy mosaicism (Kotzot 2008). UPD is known to be a contributor to rare genetic diseases and its identification is an important part of the search for disease-causing variations.…”

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confidence: 99%

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A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

et al. 2013

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Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child–mother–father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation.

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Section: à323mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

et al. 2013

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“…This simultaneous occurrence of both abnormalities is particularly common when a marker chromosome, whole chromosome aneuploidy (often mosaic) or Robertsonian translocation, is observed. [4][5][6] It has been suggested that more than a third of cases of UPD are the likely outcome of or are associated with a chromosomal abnormality. 6 Therefore, the chromosomal contribution to UPD formation is a more common phenomenon than commonly perceived.…”

Section: Introductionmentioning

confidence: 99%

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements

et al. 2014

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Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare. Replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) are recent models predicted to induce structural rearrangements and gene dosage aberrations; however, supportive evidence in humans for oneended DNA break repair coupled with MMBIR giving rise to interstitial copy number gains and distal loss of heterozygosity has not been documented. We report on the identification and characterization of two cases with interstitial triplication followed by uniparental isodisomy (isoUPD) for remainder of the chromosomal arm. Case 1 has a triplication at 9q21.11-q21.33 and segmental paternal isoUPD for 9q21.33-qter, and presented with citrullinemia with a homozygous mutation in the argininosuccinate synthetase gene (ASS1 at 9q34.1). Case 2 has a triplication at 22q12.1-q12.2 and segmental maternal isoUPD 22q12.2-qter, and presented with hearing loss, mild dysmorphic features and bilateral iris coloboma. Interstitial triplication coupled with distal segmental isoUPD is a novel finding that provides human evidence for one-ended DNA break and replication-mediated repair. Both copy number gains and isoUPD may contribute to the phenotype. Significantly, these cases represent the first detailed genomic analysis that provides support for a MMBIR mechanism inducing copy number gains and segmental isoUPD in tandem.

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“…The recurrence risk for UPD and therefore the same recessive condition in a subsequent child in general is believed to be so low that invasive prenatal diagnosis is not generally indicated. 28 The parents of patient 1 are past reproductive age, however, the parents of patient 2 did opt for prenatal diagnosis for the c.533G4A (p.W178X) mutation in their next child. Considering that the patient appeared to have uniparental isodisomy due to non-disjunction in the maternal germline, and that the couple had another child with a 48,XXXY karyotype, also a chromosome abnormality consistent with non-disjunction in the mother, it may be that there are additional genetic factors in this family predisposing to such events.…”

Section: Discussionmentioning

confidence: 99%

Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

et al. 2011

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Mitochondrial DNA (mtDNA) depletion syndrome encompasses a heterogeneous group of disorders characterized by a reduction in the mtDNA copy number. We identified two patients with clinical presentations consistent with mtDNA depletion syndrome (MDS), who were subsequently found to have apparently homozygous point mutations in TYMP and DGUOK, two of the nine nuclear genes commonly associated with these disorders. Further sequence analyses of parents indicated that in each case only one parent; the mother of the first and the father of the second, was a heterozygous carrier of the mutation identified in the affected child. The presence of underlying deletions was ruled out by use of a custom target array comparative genomic hybridization (CGH) platform. A high-density single-nucleotide polymorphism (SNP) array analysis revealed that the first patient had a region of copy-neutral absence of heterozygosity (AOH) consistent with segmental isodisomy for an 11.3 Mb region at the long-arm terminus of chromosome 22 (including the TYMP gene), and the second patient had results consistent with complete isodisomy of chromosome 2 (where the DGUOK gene is located). The combined sequencing, array CGH and SNP array approaches have demonstrated the first cases of MDS due to uniparental isodisomy. This diagnostic scenario also demonstrates the necessity of comprehensive examination of the underlying molecular defects of an apparently homozygous mutation in order to provide patients and their families with the most accurate molecular diagnosis and genetic counseling.

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Complex and segmental uniparental disomy updated

Abstract: ABSTRACT

Cited by 115 publications

References 146 publications

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements

Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

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