scholarly journals Prenatal diagnosis of complete paternal uniparental isodisomy for chromosome 3: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiufen Bu ◽  
Xu Li ◽  
Shihao Zhou ◽  
Liangcheng Shi ◽  
Xuanyu Jiang ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Rare Condition ◽  
Normal Karyotype ◽  
Chromosome 3 ◽  
Uniparental Isodisomy ◽  
Normal Ultrasound ◽  
Physical Findings

Abstract Background Uniparental disomy (UPD) is defined as an inheritance of two chromosomes from only one of the parents with no representative copy from the other. Paternal-origin UPD of chromosome 3 is a very rare condition, with only five cases of paternal UPD(3) reported. Case presentation Here, we report a prenatal case that is only the second confirmed paternal UPD(3) reported with no apparent disease phenotype. The fetus had a normal karyotype and normal ultrasound features throughout gestation. Copy neutral regions of homozygosity on chromosome 3 were identified by single nucleotide polymorphism (SNP) array. Subsequent SNP array data of parent–child trios showed that the fetus carried complete paternal uniparental isodisomy (isoUPD) of chromosome 3. The parents decided to continue with the pregnancy after genetic counseling, and the neonate had normal physical findings at birth and showed normal development after 1.5 years. Conclusions These findings provided further evidence to confirm that there were no important imprinted genes on paternal chromosome 3 that caused serious diseases and a reference for the prenatal diagnosis and genetic counseling of UPD(3) in the future.

scholarly journals Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report

2021 ◽  
Author(s):  
xiufen bu ◽  
Xu Li ◽  
Shihao Zhou ◽  
Liangcheng Shi ◽  
Xuanyu Jiang ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Rare Condition ◽  
Normal Karyotype ◽  
Chromosome 3 ◽  
Uniparental Isodisomy ◽  
Normal Ultrasound ◽  
Physical Findings

Abstract Background Paternal uniparental disomy (UPD) of chromosome 3 is a very rare condition. At present, only 5 cases of paternal UPD(3) has been reported. This was the second ascertained paternal UPD(3) with no apparent disease phenotype.Case presentation We hereby reported a case of a fetus with normal karyotype and normal ultrasound features at the whole gestation. A copy neutral regions of homozygosity on chromosome 3 was indentified by Single Nucleotide Polymophism array (SNP array). Subsequent SNP array data of parent–child trios showed the fetus has carried complete paternal uniparental isodisomy (isoUPD) of chromosome 3. The parents decided to continue the pregnancy after genetic counseling. The neonate had normal physical findings at birth and develops normally after 1.5 years. Conclusions The findings could provide further evidence to confirm that there was no important imprinted genes causing serious diseases on paternal chromosome 3 and provided a reference for the prenatal diagnosis and genetic counseling of UPD(3) in the future.

scholarly journals Prenatal diagnosis of 7 cases with uniparental disomy by utilization of single nucleotide polymorphism array

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lili Zhou ◽  
Zhaoke Zheng ◽  
Yunzhi Xu ◽  
Xiaoxiao Lv ◽  
Chenyang Xu ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prenatal Diagnosis ◽  
Molecular Analysis ◽  
Correct Diagnosis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 1 ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Rescue Mechanism

Abstract Background The phenotypes of uniparental disomy (UPD) are variable, which may either have no clinical impact, lead to clinical signs and symptoms. Molecular analysis is essential for making a correct diagnosis. This study involved a retrospective analysis of 4512 prenatal diagnosis samples and explored the molecular characteristics and prenatal phenotypes of UPD using a single nucleotide polymorphism (SNP) array. Results Out of the 4512 samples, a total of seven cases of UPD were detected with an overall frequency of 0.16%. Among the seven cases of UPD, two cases are associated with chromosomal aberrations (2/7), four cases (4/7) had abnormal ultrasonographic findings. One case presented with iso-UPD (14), and two case presented with mixed hetero/iso-UPD (15), which were confirmed by Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as maternal UPD (15) associated with Prader-Willi syndrome (PWS). Four cases had iso-UPD for chromosome 1, 3, 14, and 16, respectively; this is consistent with the monosomy rescue mechanism. Another three cases presented with mixed hetero/isodisomy were consistent with a trisomy rescue mechanism. Conclusion The prenatal phenotypes of UPD are variable and molecular analysis is essential for making a correct diagnosis and genetic counselling of UPD. The SNP array is a useful genetic test in prenatal diagnosis cases with UPD.

Uniparental Disomy May Be Associated with NPM Mutations in AML with a Normal Karyotype.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2310-2310
Author(s):  
Elena Serrano ◽  
Vanesa Orantes ◽  
Camino Estivill ◽  
Adriana Lasa ◽  
Salut Brunet ◽  
...  
Keyword(s):  
Complete Remission ◽  
Copy Number ◽  
Germ Line ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Copy Number Analysis ◽  
Complex Germ ◽  
Flt3 Mutations ◽  
Tandem Duplications

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders characterized by an abnormal proliferation of the myeloid precursors and a maturation block. A large proportion of AML cases have either a normal karyotype or non-recurrent chromosomal alterations. Underlying genetic lesions of some of these cases have been characterized with the discovery of MLL-internal tandem duplications, activating FLT3 mutations and NPM mutations. Loss of heterozygosity (LOH) derives from the loss of one of the two alleles at a given locus and can be a sign of inactivation of tumor-suppressor genes. We performed a high-resolution genotype analysis on DNA obtained from 19 AML patients with a normal karyotype, both at diagnosis and in samples obtained in complete remission(assessed by multiparametric flow cytometry) using the 10K SNP Array (Affymetrix). Both LOH and copy number analysis, as well as visualization of these analysis were performed by means of the dChip software (M. Lin et al., Bioinformatics (2004), 20:1233–40). A mean call rate of 96.8%. SNP array-based LOH analysis revealed that 4 patients presented large regions of homozygosity at diagnosis which were absent from samples in complete remission. In all four patients copy number analysis indicated no gross chromosomal losses or gains, as was confirmed by conventional cytogenetic analysis. Therefore, it can concluded that the LOH observed in these four patients was due to the presence of uniparental disomy. Simultaneous analysis of FLT-3 internal tandem duplications (FLT-3/ITD), FLT3- D835 mutations, NPM mutations and MLL rearrangements was performed using conventional molecular methods. Two of these patients (UPN2 and UPN12) had FLT-3/ITD in association with NPM mutations. UPN4 had a mutated form of NPM whereas in patient UPN16 FLT-3 and NPM genes were in the germ line configuration. All four cases were negative for MLL rearrangements and FLT-3-D835 mutations. These results suggest that NPM and FLT3 mutations may be associated with acquired somatic recombinations. It remains to be investigated whether there are loci preferentially involved by these events. Uniparental disomy and genetic lesions in normal karyotype AML Patient LOH FLT3 NPM D835 MLL UPN2 13q Mutated Mutated Germ line Germ line UPN4 6pter-p12.212q13.12-qter Germ line Mutated Germ line Germ line UPN12 2p Mutated Mutated Germ line Germ line UPN16 complex Germ line Germ line Germ line Germ line

scholarly journals Molecular Delineation of De Novo Small Supernumerary Marker Chromosomes in Prenatal Diagnosis, A Retrospective Study

2021 ◽  
Author(s):  
Shuang Hu ◽  
Xiangdong Kong
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
De Novo ◽  
Snp Array ◽  
Chromosome 9 ◽  
Marker Chromosomes ◽  
Number Variation ◽  
Low Coverage ◽  
Small Supernumerary Marker Chromosomes ◽  
Supernumerary Marker Chromosomes

Abstract Background To define the genotype-phenotype correlation of small supernumerary marker chromosomes (sSMCs) and conduct precise genetic counseling, we retrospectively searched and reviewed de novo sSMC cases detected during prenatal diagnosis at The First Affiliated Hospital of Zhengzhou University. Chromosome karyotypes of 20,314 cases of amniotic fluid from pregnant women were performed. For 16 samples with de novo sSMCs, 10 were subjected to single-nucleotide polymorphism (SNP) array or low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. Results Among the 10 sSMC cases, two sSMCs derived from chromosome 9, and three sSMCs derived from chromosomes 12, 18 and 22. The remaining 5 cases were not identified by SNP array or CNV-seq because they lacked euchromatin or had a low proportion of mosaicism. Four of them with a karyotype of 47,XN,+mar presented normal molecular cytogenetic results (seq[hg19] 46,XN), and the remaining patient with a karyotype of 46,XN,+mar presented with Turner syndrome (seq[hg19] 45,X). Five sSMC samples were mosaics of all 16 cases. Conclusion Considering the variable origins of sSMCs, further genetic testing of sSMCs should be performed by SNP array or CNV-seq. Detailed molecular characterization would allow precise genetic counseling for prenatal diagnosis.

Analysis of Loss of Heterozygosity in Adult Patients with De Novo Acute Myeloid Leukemia and Normal Karyotype.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 806-806 ◽  
Author(s):  
Christian Schon ◽  
Lars Bullinger ◽  
Frank G. Rucker ◽  
Konstanze Dohner ◽  
Hartmut Dohner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signal Intensity ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Intensity Data ◽  
Chromosome 13 ◽  
Acute Myeloid

Abstract A large proportion of acute myeloid leukemia (AML) exhibits a normal karyotype in which the underlying pathomechanisms still have to be determined. Novel techniques like arrayCGH or single nucleotide polymorphism (SNP) chip analysis allow the identification and characterization of molecular rearrangements at the sub-megabase level. Recently, the application of genome-wide SNP array technology revealed frequent uniparental disomy (UPD) in approximately 20% of AML suggesting that UPD represents a nonrandom event in leukemogenesis. Uniparental disomy is acquired by somatic recombination and therefore not accessible by conventional cytogenetic methods or arrayCGH. In this study we analyzed DNA from AML patients with normal karyotype for the presence of LOH. SNP analysis was performed on the Mapping 100k GeneChip (Affymetrix, Santa Clara, CA). DNA was extracted from paired samples of 56 de novo AML patients with normal karyotype at diagnosis and in complete remission, respectively. Signal intensity data were analyzed by the GCOS GeneChip analysis software and statistical analysis of SNP call data was performed by the dChipSNP software. In addition, standard mutation screening of the genes encoding NPM1, FLT3, CEBPA, MLL and NRAS was performed in all cases. Using the 100k SNP array, a mean SNP call rate of 98.2% was reached, resulting in > 110,000 SNP genotype calls per sample. Signal intensity data analysis revealed submicroscopic chromosomal deletions resulting in hemizygosity in three patients. Patient 1 had a single 2 Mb deletion in chromosomal band 3p14.1, patient 2 had two small deletions affecting chromosome 12q23 and 12p13, the latter encompassing the ETV6 locus, and patient 3 had two small deletions within the long arm of chromosome 8. Besides these small chromosomal regions of copy number alterations, we found 4 large stretches of somatically acquired homozygosity without numeric alterations, affecting chromosome 6 (6p21 to 6 pter and 6q26 to 6 qter), chromosome 11 (11p12 to 11pter) and chromosome 13 (13q11 to 13qter). Noteworthy, in the case with uniparental disomy of chromosome 13, we could detect a homozygous FLT3-ITD mutation, supporting the findings that acquired isodisomy for chromosome 13 is common in AML, and associated with FLT3-ITD mutations (Griffiths et al., Leukemia, 2005). In summary, high resolution SNP assay technology in AML patients with normal karyotype allowed the identification of distinct chromosomal regions affected by UPD, supporting the postulated nonrandom mechanism of acquired mitotic recombination events in AML. Besides known chromosomal regions known to be affected by genomic aberrations in AML, we found additional submicroscopic chromosomal aberrations in cases with normal karyotype. Analysis of larger patient series will allow the identification of novel regions of interest harboring genes that might be involved in the pathogenesis of AML.

A case of paternal uniparental isodisomy for chromosome 7 associated with overgrowth

2018 ◽  
Vol 55 (8) ◽  
pp. 567-570 ◽  
Author(s):  
Akie Nakamura ◽  
Koji Muroya ◽  
Hiroko Ogata-Kawata ◽  
Kazuhiko Nakabayashi ◽  
Keiko Matsubara ◽  
...  
Keyword(s):  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 7 ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Tall Stature ◽  
Methylation Analysis ◽  
Inherited Disorders ◽  
First Case ◽  
Uniparental Isodisomy

BackgroundPaternal uniparental disomy for chromosome 7 (upd(7)pat) is extremely rare, and only four cases have been previously reported. As these cases were accompanied by autosomal-recessive disorders which are likely to be involved in growth restriction, the relevance of upd(7)pat to the overgrowth phenotype remains unclear. Here we describe one case of upd(7)pat with no additional genetic diseases, which may answer the question.MethodsA 5-year-old Japanese boy presented with a tall stature of unknown causes. To detect the genetic cause of the tall stature, we performed Sanger sequencing, targeted resequencing, comparative genomic hybridisation and single-nucleotide polymorphism (SNP) array analyses, methylation analysis and microsatellite analysis.ResultsWe could not detect pathogenic variants in causative genes for overgrowth syndrome or apparent copy number alterations. DNA methylation analysis revealed hypomethylation at the GRB10, PEG1 and PEG10 differentially methylated regions. SNP array and microsatellite analyses suggested paternal uniparental isodisomy for chromosome 7. Furthermore, we could not identify homozygous mutations of known causative genes for inherited disorders on chromosome 7.ConclusionWe report the first case of upd(7)pat with an overgrowth phenotype.

Enhancement of Cytogenetic Diagnosis of Myeloid Disorders through Application of SNP-Array-Based Karyotyping.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 108-108 ◽  
Author(s):  
Lukasz P. Gondek ◽  
Ramon Tiu ◽  
Marcin Wlodarski ◽  
Christine O’Keefe ◽  
Michael McDevitt ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Germ Line ◽  
Copy Number Variants ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Disease Process ◽  
Normal Karyotype ◽  
Diagnostic Value ◽  
Differential Analysis ◽  
The Impact

Abstract Cytogenetic testing improves diagnosis in myeloid disorders; chromosomal (chr) aberrations have important clinical implications. SNP arrays (SNP-A) can be applied for karyotyping with a superb resolution of unbalanced defects and detection of uniparental disomy (UPD). We stipulated that SNP-A will enhance diagnostic value of metaphase cytogenetics (MC) and uncover new random/recurrent lesions. We applied 250K SNP-A to analysis of 76 controls and 318 patients, including 95 MDS, 64 AA, 20 PNH, 48 MDS/MPD, and AML both as primary (N=32) and secondary (N=59). Multiple samples were obtained in 13 patients. Minimal clonal size detectable by SNP-A was 25–50% by dilution studies. Repetitive testing resulted in congruent results; analysis of chr X in males showed >99% fidelity. To obtain reference, deletions and duplications seen in controls were analyzed. These abnormalities correspond to germ line encoded copy number variants (CNV). In patients such CNV were not deemed pathogenic. SNP-A confirmed 82% of unbalanced chr lesions detected by MC; discordant cases included defects involving smaller clones (<8/20 metaphases) and aberrations of Y. SNP-A allowed for detection of defects in 63% vs. 37% by MC, including 77% vs. 58% in MDS, 75% vs. 37% in MDS/MPD, 33% vs. 0% in AA, 30% vs. 0% in PNH, 59% vs. 31% in AML and 76% vs. 53% in sAML. New lesions were confirmed by paired SNP-A and microsatellite analysis. Concurrent analysis of blood and marrow showed concordant results suggesting utility of SNP-A performed on blood. Serially followed patients N=6, showed occurrence of new lesions (del(4)(q) and del(7)(q)) and earlier detection of the chr aberrations. In sAML, differential analysis of blasts and granulatocytes revealed occurrence of new lesions e.g., UPD6 or 7. In both MDS and AML, UPD of various chrs was present in 20% of patients and found in up to 35% of MDS/MPD (in addition to 9p involving also chrs 6,7,11 & 14). Other newly detected lesions included isolated/recurrent microdeletions and duplications involving genes such as AML1 or Ftl3 among others. Clinical utility of SNP-A depends on whether SNP-A karyotypig will have impact on disease parameters. In all groups tested the newly detected lesions showed impact on overall survival. While the detailed results will be a subject of our presentation, survival analysis in AML can illustrate our point; cases with a normal karyotype showed superior OS to those with newly detected defects (21 vs. 6 mo, p=.05). Similarly, new additional lesions worsen the survival as compared to those with confirmed MC (3 vs. 10 mo, p=.004). The impact on OS was also established for some of the new recurrent lesions such as UPD7q (3 vs. 39 mo, p=.002). Clinical relevance of SNP-A karyotyping is also demonstrated in AA; it may help to distinguish AA from hypocellular MDS (clonal chr. defects, including UPD, occur in 33% of AA patients), AA with normal SNP-A testing showed superior response to immunosuppression as compared to patients with a totally normal karyotype. Aside of the clinical relevance, new overlapping/recurrent lesions point towards genes involved in the disease process. We conclude that SNP-A karyotyping may enhance MC in diagnosis of chr. defects and allow for a better clinical correlations of the defects with the phnenotypic and clinical features.

Genome-Wide Micro-Deletions and Amplifications Acquired at Relapse in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 166-166 ◽  
Author(s):  
Manoj Raghavan ◽  
Manu Gupta ◽  
Tracy Chaplin ◽  
Sabah Khalid ◽  
T. Andrew Lister ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
P Value ◽  
Copy Number Changes ◽  
Acute Myeloid

Abstract Abstract 166 Recurrence of acute myeloid leukemia AML has a poor prognosis with only 20% of adults surviving to 5 years. Therefore it is of importance to identify molecular changes that explain the pathogenesis of relapsed AML. Previous studies had not identified consistently acquired cytogenetic changes at relapse. Recently, acquired uniparental disomy due to mitotic recombination was described in 40% of relapsed AML (Raghavan et al 2008). Most of the events lead to homozygosity for FLT3 mutations. This study aimed to discover if there are further genetic abnormalities acquired at disease recurrence that cannot be identified by conventional cytogenetics, i.e. microdeletions or gains. Twenty-one presentation and relapse paired AML patient blood and marrow samples were stored with consent at St Bartholomew's Hospital, London. Eleven patient samples had a normal karyotype at diagnosis, two had favourable prognosis cytogenetics (inv(16) and t(8;21)) and others had varying numerical cytogenetic abnormalities and rearrangements associated with an intermediate prognosis. DNA from the samples was analysed by array based high-resolution single nucleotide polymorphism (SNP) genotyping (Affymetrix Human SNP array 6.0). Data was analysed using Partek Genome Browser (Partek, MO). In all cases, the leukemia infiltrate of the marrow or blood was greater than 60% and most cases were greater than 90% allowing accurate identification of DNA copy number changes. Abnormalities of a size that would be identified by cytogenetics were disregarded. Using segmentation analysis using a p-value less than 0.001, over 400 microdeletions and gains were detected that were acquired at relapse in the 21 pairs. Each of the copy number changes was less than 2 megabases in size. One AML sample with a normal karyotype at diagnosis and trisomy 8 and add(9)(q34) at relapse had not acquired any microdeletions or gains. In contrast, in other samples as many as 69 microdeletions/gains were detected. There was no correlation between increased complexity of the karyotype of the leukemia and the number of microdeletions/gains. Several of the acquired microdeletions/gains were in regions containing genes known to be involved in AML, including a deletion of 234Kb at 13q12.2 involving FLT3 and CDX2, and an acquired deletion at 21p11.2 of 150Kb involving exons encoding the runt domain of RUNX1. Another copy number gain was detected at the MLL locus, suggestive of partial tandem duplication. Other detected locations are in Table 1.Table 1Location by cytobandCopy number changeSize / KbP valueGene13q12.2Deletion23410−33FLT3, CDX221q22.12Deletion15010−13RUNX111q23.3Gain5.10.0099MLL11p15.4Gain830.00001NUP9817q21.31Deletion8.00.0007BRCA1The results indicate that recurrent AML may be associated with the deletion or gain of several genes involved in leukaemogenesis. Many other locations are involved throughout the genome, suggesting at least some of these are also involved in the clonal evolution of the leukaemia at recurrence. Further studies should identify novel genes from these regions involved in the pathogenesis of AML. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document