Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Contribution of uniparental disomy in a clinical trio exome cohort of 2675 patients.

ABSTRACT:

Background

Uniparental disomy (UPD) is the inheritance of two homologous chromosomes from the same parent. UPD may result in clinical phenotypes when occurring on chromosomes with specific imprinting pattern, when leading to homozygosity of a deleterious recessive allele inherited from one carrier parent, or when associated with a mosaic aneuploidy. Due to the importance of UPD in genetic disease etiology, UPD analysis has started to be implemented in the context of exome sequencing (ES) or genome sequencing.

Methods

We developed an in-house algorithm TRIPS (Trio Parentage/UPD Studies) to identify UPD events in trio ES cases. This method identifies regions with uniparental inheritance by utilizing the trio genotyping data obtained from the concurrent SNP array to delineate the parental origin of the SNPs in the proband.

Results

We identified 16 UPD events from 2675 ES trios. Among those, four events led to imprinting disorders, seven unmasked a pathogenic/likely pathogenic variant in a recessive disease gene, and two were consistent with a mosaic genome wide paternal UPD pattern. Twelve of these UPD events directly contributed to the molecular diagnosis of the patients.

Conclusion

Our study demonstrated the contribution of UPD to the molecular diagnosis in one clinical ES cohort, thus UPD analysis should be incorporated into routine clinical ES interpretation.

SUBMITTER: Wang L

PROVIDER: S-EPMC8606208 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Uniparental disomy in a population of 32,067 clinical exome trios.

Project description:PurposeData on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis.MethodsWe analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed.ResultsNinety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22).ConclusionWhole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.

| S-EPMC8187148 | biostudies-literature

Cytogenetic contribution to uniparental disomy (UPD).

Project description:Uniparental disomy (UPD) is often considered as an event to be characterized exclusively by molecular genetic or epigenetic approaches. This review shows that at least one third of UPD cases emerge in connection with or due to a chromosomal rearrangement. Thus, additional (molecular) cytogenetic characterization of UPD cases is essential. Up to now > 1,100 UPD cases detected in clinical, non-tumor cases are reported in the literature. Recently, these cases were summarized in a regularly updated, freely available online database http://www.med.uni-jena.de/fish/sSMC/00START-UPD.htm. Based of this, here the presently known imprinting syndromes, the chromosomal contribution to UPD phenomenon, and the cytogenetic subgroups of UPD, including cases with normal, abnormal balanced or unbalanced karyotype (like e.g. small supernumerary marker chromosomes and Robertsonian translocations) and segmental UPD are reviewed. Furthermore, chromosome fragmentation as a possible mechanism of trisomic rescue is discussed, which might help to explain the observed 1:9 rate of maternal versus paternal UPD present in cases with original trisomic karyotypes. Overall, as UPD is more but an interesting rarity, the genetic background of each "UPD-patient" needs to be characterized besides by molecular methods, also by molecular cytogenetics in detail.

| S-EPMC2853554 | biostudies-literature

Accurate detection of clinically relevant uniparental disomy from exome sequencing data.

Project description:PurposeUniparental disomy (UPD) is the rare occurrence of two homologous chromosomes originating from the same parent and is typically identified by marker analysis or single-nucleotide polymorphism (SNP)-based microarrays. UPDs may lead to disease due to imprinting effects, underlying homozygous pathogenic variants, or low-level mosaic aneuploidies. In this study we detected clinically relevant UPD events in both trio and single exome sequencing (ES) data.MethodsUPD was detected by applying a method based on Mendelian inheritance errors to a cohort of 4912 ES trios (all UPD types) and by using median absolute deviation-scaled regions of homozygosity to a cohort of 29,723 single ES samples (isodisomy only).ResultsAs positive controls, we accurately identified three mixed UPD, three isodisomy, as well as two segmental UPD events that were all previously reported by SNP-based microarrays. In addition, we identified three segmental UPD and 11 isodisomy events. This resulted in a novel diagnosis based on imprinting for one patient, and adjusted genetic counseling for another patient.ConclusionUPD can easily be identified using both single and trio ES and may be clinically relevant to patients. UPD analysis should become routine in clinical ES, because it increases the diagnostic yield and could affect genetic counseling.

| S-EPMC7118024 | biostudies-literature

Uniparental disomy in Robertsonian translocations: strategies for uniparental disomy testing.

Project description:Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy and thus uniparental disomy (UPD). Chromosomes 14 and 15 are imprinted with expression of genes dependent on the parental origin of the chromosome. Correction of a trisomic or monosomic conceptus for chromosomes 14 or 15 would lead to one of the established UPD 14mat/pat or UPD 15 (Prader-Willi/Angelman) syndromes (PWS/AS). In view of this, prenatal UPD testing should be considered for balanced carriers of a ROB, fetuses with a familial or de novo balanced ROB that contains chromosome 14 or 15 or with a normal karyotype when a parent is a carrier of a balanced ROB with a 14 or 15. Individuals with congenital anomalies and an abnormal phenotype and carry a ROB involving the two imprinted chromosomes should also be UPD tested.

| S-EPMC4729106 | biostudies-literature

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

Project description: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.

| S-EPMC3975066 | biostudies-literature

Uniparental disomy: expanding the clinical and molecular phenotypes of whole chromosomes.

Project description:Uniparental disomy (UPD) refers to as both homologous chromosomes inherited from only one parent without identical copies from the other parent. Studies on clinical phenotypes in UPDs are usually focused on the documented UPD 6, 7, 11, 14, 15, and 20, which directly lead to imprinting disorders. This study describes clinical phenotypes and genetic findings of three patients with UPD 2, 9, and 14, respectively. Chromosomal microarray (CMA), UPDtool, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and whole-exome sequencing (WES) analysis were performed to characterize the genetic etiology. The CMA revealed a homozygous region involving the whole chromosome 2 and 9, a partial region of homozygosity in chromosome 14. UPD-tool revealed a paternal origin of the UPD2. MS-MLPA showed hypomethylation of imprinting gene MEG3 from maternal origin in the UPD14 case. In addition, UPD14 case displayed complex symptoms including growth failure, hypotonia and acute respiratory distress syndrome (ARDS), accompanied by several gene mutations with heterozygous genotype by WES analysis. Furthermore, we reviewed the documented UPDs and summarized the clinical characteristics and prognosis. This study highlighted the importance to confirm the diagnosis and origin of UPD using genetic testing. Therefore, it is suggested that expanding of the detailed phenotypes and genotypes provide effective guidance for molecule testing and genetic counseling, and promote further biological investigation to the underlying mechanisms of imprinted disorders and accompanied copy number variations.

| S-EPMC10582337 | biostudies-literature

Reciprocal uniparental disomy in yeast.

Project description:In the diploid cells of most organisms, including humans, each chromosome is usually distinguishable from its partner homolog by multiple single-nucleotide polymorphisms. One common type of genetic alteration observed in tumor cells is uniparental disomy (UPD), in which a pair of homologous chromosomes are derived from a single parent, resulting in loss of heterozygosity for all single-nucleotide polymorphisms while maintaining diploidy. Somatic UPD events are usually explained as reflecting two consecutive nondisjunction events. Here we report a previously undescribed mode of chromosome segregation in Saccharomyces cerevisiae in which one cell division produces daughter cells with reciprocal UPD for the same pair of chromosomes without an aneuploid intermediate. One pair of sister chromatids is segregated into one daughter cell and the other pair is segregated into the other daughter cell, mimicking a meiotic chromosome segregation pattern. We term this process "reciprocal uniparental disomy."

| S-EPMC3382553 | biostudies-other

Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias.

Project description:BackgroundThe genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent. Detection of UPD-caused homozygous disease-causing variants is detrimental to accurate genetic counseling. Whole-exome sequencing can allow for the detection of such events.MethodsWe systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.ResultsOne hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease-causing mutation in the SPG35 disease gene was then identified within this region.ConclusionThis study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.

| S-EPMC5441426 | biostudies-literature

Uniparental disomy: expanding the clinical and molecular phenotypes of whole chromosomes

Project description:Uniparental disomy (UPD) refers to as both homologous chromosomes inherited from only one parent without identical copies from the other parent. Current knowledge of the phenotypes is associated with imprinting disorders or autosomal recessive mutations. Recent studies had reported that UPD for chromosomes 6, 7, 11, 14, 15, and 20 accompanied with definite imprinted disorders. However, the phenotypes and outcomes of UPD with other chromosomes have not been completely identified. Herein, we combined three remarkable UPD patients involving different chromosomes and presented their phenotypes. The chromosomal microarray (CMA) demonstrated a whole homozygous region on chromosome 2 in patient A, on chromosome 9 in patient B, accompanied by a gain mosaic region (ratio:22%) of 19.18Mb in 9p22.2p13.2, and a LOH region on 14q23.2q32.12 and several genes with compound heterozygous mutation were detected in patient C

2024-06-30 | GSE235878 | GEO

Somatic uniparental disomy of Chromosome 16p in hemimegalencephaly.

Project description:Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning ZNF597 was identified, which results in increased expression of ZNF597 mRNA and protein in the brain tissue of the second case. Enhanced mTOR signaling was observed in tissue specimens from both patients. We speculate that overexpression of maternally expressed ZNF597 led to aberrant hemispheric development in the patient with somatic UPD of Chromosome 16p possibly through modulation of mTOR signaling.

| S-EPMC5593155 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data