Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism
© Robberecht et al; licensee BioMed Central Ltd. 2012
Received: 17 February 2012
Accepted: 10 April 2012
Published: 10 April 2012
Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations. However, few studies have tested this assumption. Here we determined the origin of CNVs which coexist with a normal cell line in nine individuals. We show that in 2/9 the CNV originated during meiosis. The existence of two cell lines with 46 chromosomes thus resulted from two parallel trisomy rescue events during postzygotic mitoses.
KeywordsSegmental aneusomy Duplication Deletion Somatic mosaicism Constitutional Mechanism Prezygotic Mitotic Postzygotic Meiotic
For decades, knowledge about copy number variation (CNV) in the human genome was limited to microscopically visible changes. Advances in technology have led to the discovery of submicroscopic CNVs, ranging from kilobases to megabases in size and covering up to 13% of the human genome [1, 2]. These CNVs can cause recurrent genomic disorders and sporadic disease, or they can represent benign changes found in the healthy population [3, 4]. Recent studies have revealed that CNVs are not only polymorphic between unrelated individuals, but also form a frequent source of somatic variation [5, 6].
Chromosomal mosaicism is defined as the coexistence of two or more chromosomally different cell lines in an organism which developed from a single zygote. The majority of those mosaicisms are aneuploidies. Several studies investigating in vitro fertilized embryos at the preimplantation stage demonstrated a very high number of chromosomal mosaicisms in early human embryos [7–9]. While many of these embryos will not reach the stage of implantation, some do continue to develop leading to fetal mosaicisms, confined placental mosaicism or mosaic infants. Postnatally, mosaicism is detected in 0.4-1% of patients referred for genetic diagnostic screening [10–12]. A recent study revealed that mosaic aberrations are present in about 0.8% of phenotypically normal adults . In addition, mosaicism appears to be variable amongst different tissues: chromosomal aneuploidies were detected in approximately 10% of normal human brain cells .
Segmental aneuploidies make up a significant part of mosaic chromosome anomalies. Analysis of several large series of prenatal samples by karyotyping has shown that, of the 0.25-2% mosaic cases that are detected, up to a third comprise segmental imbalances [15, 16]. In postnatal clinical diagnosis of patients with developmental anomalies this increases to about half of the mosaic cases [10, 17]. The majority of mosaic segmental imbalances are marker chromosomes . A smaller number of cases have been reported to consist of mosaic segmental deletions and/or duplications, ring chromosomes and translocations that have a 46,abnormal/46,normal karyotype. In recent years various case reports have been published [18–36]. The introduction of genome wide aneuploidy detection tools with a higher resolution such as array comparative genomic hybridisation (array CGH) or SNP arrays and the collection of large patient groups have also increased the detection rate of mosaic segmental abnormalities [10, 12, 17].
For mosaic aberrations, it is intuitively assumed that the rearrangement arose postzygotically. During embryogenesis, a mitotic rearrangement in an otherwise normal diploid embryo results in a second cell line carrying a chromosomal rearrangement. Nevertheless, evidence is mounting that such rearrangements can originate during meiosis. If so, a trisomic zygote carrying the abnormal chromosome has to be rescued twice, in parallel: once loosing the normal and once loosing the abnormal chromosome. Considering that the mitotic error rate is extremely high during early embryogenesis [7–9] and that most cases of mosaic aneuploidy detected in a large cohort of patients were of mitotic origin , we reasoned that the latter mechanism might be an important mechanism by which such mosaics arise. In this study we collected nine cases with mosaic structural imbalances to determine their origin and to ascertain whether a meiotic or postzygotic origin might be more prevalent.
Combined karyotypes after conventional and molecular cytogenetic analyses
Karyotype (ISCN 2009; Mb positions mapped in hg19)
46,XX,dup(13)(q31.3q33.1)dn/46,XX.arr 13q31.3q33.1 (RP11-319 L6-RP11-564 N10)x2 ~3
46,XX,dup(15)(q25q26.3)dn/46,XX.arr 15q25.2q26.3 (RP11-365 F16-CTB-154P1)2 ~3
46,XY,dup(11)(q12.1q13.3)dn/46,XY.arr 11q12.1q13.3 (RP11-131 J4-RP11-804 L21)2 ~3
46,XY,dup(1)(q12q32.1)dn/46,XY.arr 1q12q32.1 (RP11-417 J8-RP11-383 G10)2 ~3
46,XX,der(6)t(2;6)(p23.2;qter)dn/46,XX.arr 2p25.3p23.2 (GS1-68 F18-RP11-328 L16)2 ~3
25.56 Mb/124.2 Mb
46,XX,der(10)t(9;10)(p23;q26.13)dn/46,XX.arr 9p24.3p23(40,910-13,575,891)x2 ~3, 10q26.13q26.3 (124,007,108-135,422,505)x1 ~2
13.53 Mb/11.31 Mb
46,XX.ish del(11)(q14.1q14.2)(RP11-118 L16-,RP11-157B22-)dn[21/50].arr 11q14.1q14.2(83,122,844-86,794,856)x1 ~2
46,XX.ish del(1)(q43q44)(RP11-113O11-,RP11-370 K11-)dn[25/50].arr 1q43q44(242,916,876-243,920,382)x1 ~2
Results of the STR marker analysis
For two samples, three different alleles were detected within the duplicated region indicating a meiotic origin. Polymorphic marker analysis of sample 1 revealed the presence of three different alleles for marker D13S128 (Figure 3A). Two of the alleles were inherited from the father demonstrating the paternal origin of the segmental aneusomy. At marker D13S129, still within the duplication, two alleles with a 2:1 intensity ratio were detected, including only one of the two paternal alleles (Figure 3B). The remaining markers within the duplication were not informative. In case 6, carrier of an unbalanced translocation, two markers (D1S1653 and D1S1171) spread throughout the duplicated 1q region showed three different alleles (Figure 4). The other markers on 1q had either one or two alleles. Marker D20S117 in the deleted 20p region confirmed the deletion, with a 1:2 reduced peak intensity for one of both alleles.
For the other cases, only two different alleles were identified within the duplication region. Genotyping of cases 2 to 5 within the region of duplication showed in each case only two alleles. One of both alleles clearly had a higher intensity with about a 2:1 ratio (Figure 5). For sample 5, in which array CGH revealed that the rearrangement is only present in 10 to 20% (log2 value of 0.0888) of all cells, these peak intensity differences were still present, but to a lesser extent.
To determine the origin of the deletion in cases 8 and 9, again for the SNPs that were homozygous but with a different allele in both parents in the deletion, the A and B allele ratios were determined. The analysis showed that the signal of the paternal allele was reduced in case 8 and that a maternal allele was removed in case 9. To search for evidence of a potential meiotic event, the rest of the chromosome was screened for the presence of two paternal (case 8) or two maternal alleles (case 9). Hereto, the B-allele frequencies of SNPs on the affected chromosome, but outside the somatic CNV region, were evaluated for additional haplotypes. If the deletion resulted from a meiotic event, altered B-allele frequencies would be observed, with additional values between 0 and 0.5 as well as between 0.5 and 1. No such haplotypes were detected in the regions surrounding the deletion (Figure 6B).
The combination of a normal and an aberrant cell line in these cases could, aside from mosaicism, also result from chimerism: the fusion of two cell lineages from separate fertilization events. In samples 1 to 6, the presence of chimerism was evaluated by testing four STR markers spread over different chromosomes not involved in the aberrant region. in case of a mosaic all autosomal genotypes outside the duplicated region are expected to only contain two alleles (1 maternal & 1 paternal). For chimeras, some loci would have three or four alleles, or a skewed dosage of two alleles . None of the samples showed more than two alleles on any of the markers, confirming the mosaic status of the aberration (data not shown). In cases 7 to 9, the two different genotypes present in case of chimerism would be seen as aberrant B-allele frequencies in all autosomes, with an altered ratio between the two haplotypes. No alterations in the B-allele frequency were seen in the unaffected chromosomes, thereby ruling out the possibility of chimerism.
While the origin of mosaic segmental CNVs has only rarely been investigated, two case reports support our finding that pre-zygotic rearrangements followed by multiple postzygotic trisomy rescue events can underlie segmental mosaicisms. Blouin et al. detected a mosaic de novo direct tandem duplication of 21q11.2q22.2 that resulted from a meiosis I crossover followed by an unequal sister chromatid exchange and two trisomy rescue events, similar to our case 1. The mosaic de novo unbalanced translocation with partial trisomy 16p and maternal UPD 16 reported by Schinzel et al. likely originated from a maternal trisomy 16 (MI), a subsequent postzygotic translocation of the paternal 16p segment and finally loss of the paternal chromosomes 16 in the translocated and normal cell lines [18, 32]. Even after combining our results with previous mosaic segmental cases the total study population remains small, but future studies may be able to provide additional evidence for the high frequency of multiple independent trisomy rescue events.
In conclusion, we demonstrated that in 2/9 cases, the detected mosaic segmental aberrations resulted from meiotic errors followed by multiple parallel trisomy rescue events and not from postzygotic mitotic changes. In addition, we show that the use of sensitive array technology is especially suited for the detection of mosaicism, which is clinically relevant to a patient's diagnosis.
Five cases were referred for cytogenetic/molecular investigations after clinical evaluation for dysmorphic features, whereas cases 4, 6, 8 and 9 were ascertained during prenatal diagnosis (CVS and/or amniocentesis).
Cytogenetic analyses were performed on GTG-banded metaphase chromosomes from PHA-stimulated peripheral blood lymphocytes or from CVS cells or amniocytes after standard culture and chromosome preparation protocols. Twenty metaphases with a resolution of 550 bands per haploid genome were karyotyped (ISCN 2009).
BAC microarray analysis was performed as described elsewhere . Briefly, CodeLink Bioarray System slides (Amersham Biosciences, Chalfont St.Giles, UK) were used for array construction using a 1 Mb clone set of 3 683 BAC and PAC clones. Genomic DNA from the index patient and two other patients was labelled in Cy3 and Cy5, respectively (Amersham Biosciences, Chalfont St.Giles, UK) with random prime labelling (Bioprime array CGH, Invitrogen, Sunnydale, CA) and hybridized in a 3-way experiment. Hybridization and post-hybridization washing steps were performed as previously described . Slides were scanned at 532 nm (Cy3) and 635 nm (Cy5) using a GenePix 4000B microarray scanner (Axon Instruments, Union City, CA) with the software GenePixPro 6.0. Data analysis was performed with Excel (Microsoft Inc.; Diegem, Belgium) as described . The percentage of mosaicism was calculated by dividing the mean log2 ratio of the BAC clones in the duplicated region by the log2 of a non-mosaic aberration (0.5849).
SNP array analysis was performed on Affymetrix GeneChip® Human Mapping 250 K NspI arrays (Affymetrix, Inc., Santa Clara CA, USA) containing 25-mer oligonucleotides representing a total of 262 264 SNPs. DNA digestion, labeling and hybridization were performed according to the manufacturer's protocol. After hybridization, arrays were washed and stained on the Affymetrix GeneChip fluidics station 450 and scanned using the Affymetrix GeneChip® Scanner 3000 7 G. Data analysis was performed using Copy Number Analyzer for GeneChip version 2.0 (CNAG 2.0)  and Genotyping Console™ Software (Affymetrix, Inc.).
Fluorescent in situ hybridization
To confirm aberrations found by microarray, FISH was performed with BAC probes as described , using an optical fluorescence microscope (Olympus U-SPT, BX51, Japan) with selective filters equipped with CytoVision® software (Applied Imaging, Genetix, Gateshead, UK).
SNP cluster determination
For determining the parental origin of the DNA copy number aberrations by a SNP-cluster strategy, normalized SNP A and B allele intensities as well as SNP genotype calls were computed using Affymetrix power tools (APT-1.10.1) in combination with the Birdseed command . Besides the described trio datasets, in-house produced Affymetrix 250 K SNP NspI data from 102 additional DNA samples were co-processed for accurate SNP cluster and genotype determination. Subsequently, the probe intensities and genotype calls for SNPs within the regions of interest were retrieved for all DNA samples and interpreted by custom R-code  in which patient and parental SNP-probe intensities are visualised in the Birdseed SNP clusters from the 102 individuals.
B-allele frequency plots
To generate the B-allele frequency (BAF) plots, copy number analysis of the SNP array data was performed using the Affymetrix power tools BRLMM, a modified version of RLMM  and the pennCNV  algorithm. These data were subsequently further interpreted and visualized in BAF and logR ratio plots by the genoCN algorithm .
Polymorphic microsatellite marker analysis
Polymorphic microsatellite markers made up of dinucleotide (CA)n repeats (short tandem repeats or STRs) were selected from the Ensembl  and UCSC  genome browser databases and the oligonucleotides were purchased from Eurogentec S.A. (Seraing, Belgium) and Pharmacia Biotech (Uppsala, Sweden). Genomic DNA was extracted from peripheral blood leukocytes, amniocytes or CVS cells of the patients and their parents according to standard procedures and CA repeats spaced along the involved chromosomes were amplified by polymerase chain reaction (PCR). DNA extracted from skin fibroblasts was also included in the analysis in case the mosaicism was encountered in fibroblasts.
After PCR amplification of the STRs, fragments were analyzed by gel electrophoresis. Automated fragment sizing was performed on the ABI Prism 3100 Genetic Analyzer (Applied Biosystems, Nieuwerkerk a/d Ijssel, the Netherlands), using software GeneScan or Genemapper v4.0 (Applied Biosystems, Nieuwerkerk a/d Ijssel, The Netherlands).
This work has been made possible by an IWT (SBO 60848) and FWO grant G.0320.07.
- Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang YJ, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, MacArthur DG, MacDonald JR, Onyiah I, Pang AWC, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME: Origins and functional impact of copy number variation in the human genome. Nature 2010, 464: 704–712. 10.1038/nature08516PubMed CentralView ArticlePubMedGoogle Scholar
- Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi MY, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M: Large-scale copy number polymorphism in the human genome. Science 2004, 305: 525–528. 10.1126/science.1098918View ArticlePubMedGoogle Scholar
- Lupski JR: Genomic rearrangements and sporadic disease. Nat Genet 2007, 39: S43-S47. 10.1038/ng2084View ArticlePubMedGoogle Scholar
- Shaw CJ, Lupski JR: Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 2004, 13: R57-R64. 10.1093/hmg/ddh073View ArticlePubMedGoogle Scholar
- Bruder CEG, Piotrowski A, Gijsbers AACJ, Andersson R, Erickson S, de Stahl TD, Menzel U, Sandgren J, von Tell D, Poplawski A, Crowley M, Crasto C, Partridge EC, Tiwari H, Allison DB, Kornorowski J, van Ommen GJB, Boomsma DI, Pedersen NL, den Dunnen JT, Wirdefeldt K, Dumanski JP: Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 2008, 82: 763–771. 10.1016/j.ajhg.2007.12.011PubMed CentralView ArticlePubMedGoogle Scholar
- Piotrowski A, Bruder CEG, Andersson R, de Stahl TD, Menzel U, Sandgren J, Poplawski A, von Tell D, Crasto C, Bogdan A, Bartoszewski R, Bebok Z, Krzyzanowski M, Jankowski Z, Partridge EC, Komorowski J, Dumanski JP: Somatic mosaicism for copy number variation in differentiated human tissues. Hum Mutat 2008, 29: 1118–1124. 10.1002/humu.20815View ArticlePubMedGoogle Scholar
- Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F, Fryns JP, Verbeke G, D'Hooghe T, Moreau Y, Vermeesch JR: Chromosome instability is common in human cleavage-stage embryos. Nat Med 2009, 15: 577–583. 10.1038/nm.1924View ArticlePubMedGoogle Scholar
- Voullaire L, Slater H, Williamson R, Wilton L: Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum Genet 2000, 106: 210–217. 10.1007/s004390051030View ArticlePubMedGoogle Scholar
- Wells D, Delhanty JDA: Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod 2000, 6: 1055–1062. 10.1093/molehr/6.11.1055View ArticlePubMedGoogle Scholar
- Ballif BC, Rorem EA, Sundin K, Lincicum M, Gaskin S, Coppinger J, Kashork CD, Shaffer LG, Bejjani BA: Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A 2006, 140: 2757–2767.View ArticlePubMedGoogle Scholar
- Conlin LK, Thiel BD, Bonnemann CG, Medne L, Ernst LM, Zackai EH, Deardorff MA, Krantz ID, Hakonarson H, Spinner NB: Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 2010, 19: 1263–1275. 10.1093/hmg/ddq003PubMed CentralView ArticlePubMedGoogle Scholar
- Cheung SW, Shaw CA, Scott DA, Patel A, Sahoo T, Bacino CA, Pursley A, Li J, Erickson R, Gropman AL, Miller DT, Seashore MR, Summers AM, Stankiewicz P, Chinault AC, Lupski JR, Beaudet AL, Sutton VR: Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet A 2007, 143A: 1679–1686. 10.1002/ajmg.a.31740View ArticlePubMedGoogle Scholar
- Rodriguez-Santiago B, Malats N, Rothman N, Armengol L, Garcia-Closas M, Kogevinas M, Villa O, Hutchinson A, Earl J, Marenne G, Jacobs K, Rico D, Tardon A, Carrato A, Thomas G, Valencia A, Silverman D, Real FX, Chanock SJ, Perez-Jurado LA: Mosaic Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome. Am J Hum Genet 2010, 87: 129–138. 10.1016/j.ajhg.2010.06.002PubMed CentralView ArticlePubMedGoogle Scholar
- Iourov IY, Vorsanova SG, Liehr T, Yurov YB: Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: Differential expression and pathological meaning. Neurobiol Dis 2009, 34: 212–220. 10.1016/j.nbd.2009.01.003View ArticlePubMedGoogle Scholar
- Ledbetter DH, Zachary JM, Simpson JL, Golbus MS, Pergament E, Jackson L, Mahoney MJ, Desnick RJ, Schulman J, Copeland KL, Verlinsky Y, Yangfeng T, Schonberg SA, Babu A, Tharapel A, Dorfmann A, Lubs HA, Rhoads GG, Fowler SE, Delacruz F: Cytogenetic Results from the United-States Collaborative Study on Cvs. Prenat Diagn 1992, 12: 317–345. 10.1002/pd.1970120503View ArticlePubMedGoogle Scholar
- Hsu LYF, Yu MT, Richkind KE, Vandyke DL, Crandall BF, Saxe DF, Khodr GS, Mennuti M, Stetten G, Miller WA, Priest JH: Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: A collaborative study. Prenat Diagn 1996, 16: 1–28. 10.1002/(SICI)1097-0223(199601)16:1<1::AID-PD816>3.0.CO;2-WView ArticlePubMedGoogle Scholar
- Hoang S, Ahn J, Mann K, Bint S, Mansour S, Homfray T, Mohammed S, Ogilvie CM: Detection of mosaicism for genome imbalance in a cohort of 3,042 clinical cases using an oligonucleotide array CGH platform. Eur J Med Genet 2010, 54: 121–129.View ArticlePubMedGoogle Scholar
- Blouin JL, Aurias A, Creaugoldberg N, Apiou F, Alcaideloridan C, Bruel A, Prieur M, Kraus J, Delabar JM, Sinet PM: Cytogenetic and Molecular Analysis of A Denovo Tandem Duplication of Chromosome-21. Hum Genet 1991, 88: 167–174.View ArticlePubMedGoogle Scholar
- De Silva D, Massie D, Drummond J, Couzin D, Dean JCS: Mosaicism for a tandem duplication dup(1)(q12q22) in an 18 year old female. J Med Genet 1998, 35: 600–603. 10.1136/jmg.35.7.600PubMed CentralView ArticlePubMedGoogle Scholar
- Dixon JW, Costa T, Teshima IE: Mosaicism for Duplication 12Q (12Q13-]Q24.2) in A Dysmorphic Male Infant. J Med Genet 1993, 30: 70–72. 10.1136/jmg.30.1.70PubMed CentralView ArticlePubMedGoogle Scholar
- Erez A, Li J, Geraghty MT, Ben-Shachar S, Cooper ML, Mensing DE, Vonalt KD, Ou Z, Pursley AN, Chinault AC, Patel A, Cheung SW, Sahoo T: Mosaic Deletion 11p13 in a Child With Dopamine Beta-Hydroxylase Deficiency-Case Report and Review of the Literature. Am J Med Genet A 2010, 152A: 732–736. 10.1002/ajmg.a.33269View ArticlePubMedGoogle Scholar
- Faivre L, Viot G, Prieur M, Turleau C, Gosset P, Romana S, Munnich A, Vekemans M, Cormier-Daire V: Apparent Sotos syndrome (cerebral gigantism) in a child with trisomy 20p11.2-p12.1 mosaicism. Am J Med Genet 2000, 91: 273–276. 10.1002/(SICI)1096-8628(20000410)91:4<273::AID-AJMG6>3.0.CO;2-HView ArticlePubMedGoogle Scholar
- Gardner RJM, Dockery HE, Fitzgerald PH, Parfitt RG, Romain DR, Scobie N, Shaw RL, Tumewu P, Watt AJ: Mosaicism with A Normal-Cell Line and An Autosomal Structural Rearrangement. J Med Genet 1994, 31: 108–114. 10.1136/jmg.31.2.108PubMed CentralView ArticlePubMedGoogle Scholar
- Karaoguz MY, Biri A, Pala E, Kan D, Poyraz A, Kurdoglu M, Percin EF: A case with mosaic partial duplication of 1q: Prenatal and postmortem clinical and cytogenetic evaluations. Genet Couns 2006, 17: 197–204.PubMedGoogle Scholar
- Kotzot D, Schinzel A: Paternal meiotic origin of der(21;21)(q10;q10) mosaicism [46, XX/46, XX, der(21;21)(q10;q10),+21] in a girl with mild Down syndrome. Eur J Hum Genet 2000, 8: 709–712. 10.1038/sj.ejhg.5200520View ArticlePubMedGoogle Scholar
- Kotzot D, Martinez MJ, Bagci G, Basaran S, Baumer A, Binkert F, Brecevic L, Castellan C, Chrzanowska K, Dutly F, Gutkowska A, Karauzum SB, Krajewska-Walasek M, Luleci G, Miny P, Riegel M, Schuffenhauer S, Seidel H, Schinzel A: Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications. J Med Genet 2000, 37: 281–286. 10.1136/jmg.37.4.281PubMed CentralView ArticlePubMedGoogle Scholar
- Martinez A, Ramos S, Gonzalez-Del AA, Alcantara MA, Molina B, Carnevale A: Duplication 2p and monosomy 8p in mosaicism: clinical, molecular cytogenetic and molecular markers of a unique case. Rev Invest Clin 2007, 59: 444–448.PubMedGoogle Scholar
- Patel C, Hardy G, Cox P, Bowdin S, McKeown C, Russell AB: Mosaic Trisomy 1q: The Longest Surviving Case. Am J Med Genet A 2009, 149A: 1795–1800. 10.1002/ajmg.a.32959View ArticlePubMedGoogle Scholar
- Rauen KA, Bitts SM, Li L, Golabi M, Cotter PD: Tandem duplication mosaicism: characterization of a mosaic dup(5q) and review. Clin Genet 2001, 60: 366–370.View ArticlePubMedGoogle Scholar
- Sarri C, Gyftodimou J, Avramopoulos D, Grigoriadou M, Pedersen W, Pandelia E, Pangalos C, Abazis D, Kitsos G, Vassilopoulos D, BrondumNielsen K, Petersen MB: Partial trisomy 17q22-qter and partial monosomy Xq27-qter in a girl with a de novo unbalanced translocation due to a postzygotic error: Case report and review of the literature on partial trisomy 17qter. Am J Med Genet 1997, 70: 87–94. 10.1002/(SICI)1096-8628(19970502)70:1<87::AID-AJMG16>3.0.CO;2-TView ArticlePubMedGoogle Scholar
- Scheuerle A, Heller K, Elder F: Complete trisomy 1q with mosaic Y;1 translocation: A recurrent aneuploidy presenting diagnostic dilemmas. Am J Med Genet A 2005, 138A: 166–170. 10.1002/ajmg.a.30940View ArticlePubMedGoogle Scholar
- Schinzel A, Kotzot D, Brecevic L, Robinson WP, Dutly F, Dauwerse H, Binkert F, Baumer A, Ausserer B: Trisomy first, translocation second, uniparental disomy and partial trisomy third: A new mechanism for complex chromosomal aneuploidy. Eur J Hum Genet 1997, 5: 308–314.PubMedGoogle Scholar
- Stallings R, Vaughan D, Hall K, Joyce C, Ryan F, Barton D, Geraghty M: Mosaicism for trisomy 3q arising from an unbalanced, de novo t(3;15). J Med Genet 1997, 34: 512–514. 10.1136/jmg.34.6.512PubMed CentralView ArticlePubMedGoogle Scholar
- Zaslav AL, Fallet S, Blumenthal D, Jacob J, Fox J: Mosaicism with a normal cell line and an unbalanced structural rearrangement. Am J Med Genet 1999, 82: 15–19. 10.1002/(SICI)1096-8628(19990101)82:1<15::AID-AJMG3>3.0.CO;2-6View ArticlePubMedGoogle Scholar
- Zeng S, Patil SR, Yankowitz J: Prenatal detection of mosaic trisomy 1q due to an unbalanced translocation in one fetus of a twin pregnancy following in vitro fertilization: a postzygotic error. Am J Med Genet A 2003, 120A: 464–469. 10.1002/ajmg.a.20189View ArticlePubMedGoogle Scholar
- Tharapel AT, Michaelis RC, Velagaleti GVN, Laundon CH, Martens PR, Buchanan PD, Teague KE, Tharapel SA, Wilroy RS: Chromosome duplications and deletions and their mechanisms of origin. Cytogenet Cell Genet 1999, 85: 285–290. 10.1159/000015314View ArticlePubMedGoogle Scholar
- Ramsay M, Pfaffenzeller W, Kotze E, Bhengu L, Essop F, de Ravel T: Chimerism in Black Southern African Patients with True Hermaphroditism 46, XX/47XY,+21 and 46, XX/46, XY. Ann N Y Acad Sci 2009, 1151: 68–76. 10.1111/j.1749-6632.2008.03570.xView ArticlePubMedGoogle Scholar
- Font-Montgomery E, Stone KM, Weaver DD, Vance GH, Das S, Thurston VC: Clinical outcome and follow-up of the first reported case of Russell-Silver syndrome with the unique combination of maternal uniparental heterodisomy 7 and mosaic trisomy 7. Birth Defects Res A Clin Mol Teratol 2005, 73: 577–582. 10.1002/bdra.20174View ArticlePubMedGoogle Scholar
- Kagami M, Kato F, Matsubara K, Sato T, Nishimura G, Ogata T: Relative frequency of underlying genetic causes for the development of UPD(14)pat-like phenotype. Eur J Hum Genet 2012, in press.Google Scholar
- Mergenthaler S, Wollmann HA, Burger B, Eggermann K, Kaiser P, Ranke MB, Schwanitz G, Eggermann T: Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue. Presentation of own results and review of the literature. Ann Genet 2000, 43: 15–21. 10.1016/S0003-3995(00)00010-1View ArticlePubMedGoogle Scholar
- Vermeesch JR, Melotte C, Froyen G, Van Vooren S, Dutta B, Maas N, Vermeulen S, Menten B, Speleman F, De Moor B, Van Hummelen P, Marynen P, Fryns JP, Devriendt K: Molecular karyotyping: Array CGH quality criteria for constitutional genetic diagnosis. J Histochem Cytochem 2005, 53: 413–422. 10.1369/jhc.4A6436.2005View ArticlePubMedGoogle Scholar
- Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang LL, Hangaishi A, Kurokawa M, Chiba S, Bailey DK, Kennedy GC, Ogawa S: A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 2005, 65: 6071–6079. 10.1158/0008-5472.CAN-05-0465View ArticlePubMedGoogle Scholar
- Vermeesch JR, Mertens G, David G, Marynen P: Assignment of the Human Glypican Gene (Gpc1) to 2Q35-Q37 by Fluorescence In-Situ Hybridization. BMC Genomics 1995, 25: 327–329.View ArticleGoogle Scholar
- Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins PJ, Darvishi K, Lee C, Nizzari MM, Gabriel SB, Purcell S, Daly MJ, Altshuler D: Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 2008, 40: 1253–1260. 10.1038/ng.237PubMed CentralView ArticlePubMedGoogle Scholar
- The R Project for Statistical Computing[http://www.r-project.org/]
- Rabbee N, Speed TP: A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics 2006, 22: 7–12. 10.1093/bioinformatics/bti741View ArticlePubMedGoogle Scholar
- Wang K, Li MY, Hadley D, Liu R, Glessner J, Grant SFA, Hakonarson H, Bucan M: PennCNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007, 17: 1665–1674. 10.1101/gr.6861907PubMed CentralView ArticlePubMedGoogle Scholar
- Sun W, Wright FA, Tang ZZ, Nordgard SH, Van Loo P, Yu TW, Kristensen VN, Perou CM: Integrated study of copy number states and genotype calls using high-density SNP arrays. Nucleic Acids Res 2009, 37: 5365–5377. 10.1093/nar/gkp493PubMed CentralView ArticlePubMedGoogle Scholar
- UCSC Genome Bioinformatics[http://genome.ucsc.edu/]
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