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Special feature on copy-number variation
Short report
Mosaic trisomy 13: understanding origin using SNP array
  1. Natini Jinawath1,2,
  2. Regina Zambrano1,3,
  3. Elizabeth Wohler4,
  4. Maria K Palmquist1,5,
  5. Julie Hoover-Fong1,6,
  6. Ada Hamosh1,6,
  7. Denise A S Batista1,4,7
  1. 1Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  2. 2Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
  3. 3Department of Pediatrics, Louisiana State University Health Science Center and Children's Hospital, New Orleans, Louisiana, USA
  4. 4Kennedy Krieger Institute, Cytogenetics Laboratory, Baltimore, Maryland, USA
  5. 5Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA
  6. 6Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  7. 7Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  1. Correspondence to Dr Denise Batista, Department of Pathology, Johns Hopkins Medical Institutions, 600 N Wolfe Street, Park SB202, Baltimore, MD 21287, USA; dbatist1{at}jhmi.edu

Abstract

Background Trisomy 13 occurs in 1/10 000–20 000 live births, and mosaicism accounts for 5% of these cases. Phenotype and outcome of mosaic trisomy 13 are variable and poorly understood. Microsatellite analyses of trisomy 13 have indicated the high incidence of maternal meiotic origin and reduced recombination, but no study has focused on mosaic trisomy 13 in live born patients.

Methods and results Single-nucleotide polymorphism (SNP) array, fluorescence in situ hybridisation and bioinformatics analyses were performed in three cases of mosaic trisomy 13. Two cases of complete mosaic trisomy 13 originated from meiosis I non-disjunction followed by trisomic rescue; one had crossovers resulting in segmental uniparental disomy in the disomic line, and one had no crossover. Mosaicism for partial trisomy 13 in the third complex case either arose from meiosis II non-disjunction without crossover or in early mitosis followed by anaphase lags. The extra chromosome 13 was maternal in origin in all three cases. Mosaicism percentage calculated from B allele frequencies ranged from 30 to 50.

Conclusions Genotypes and copy number information provided by SNP array allow determination of parental origin and uniparental disomy status and direct quantification of mosaicism. Such information may lead to a better understanding of mechanisms underlying mosaic aneuploidies and the observed phenotypic variability and better prediction of recurrent risk.

  • Trisomy 13
  • mosaicism
  • SNP array
  • uniparental disomy
  • non-disjunction
  • diagnostics tests
  • getting research into practice
  • genetics
  • cytogenetics
  • molecular genetics

https://doi.org/10.1136/jmg.2010.083931

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    Trisomy 13 is the third most common autosomal trisomy among newborns. The majority of trisomy 13 conceptuses suffer prenatal loss, and 80% of the live born infants die within the first month.1 In mosaic trisomy 13, the phenotype and clinical outcome vary greatly, ranging from normal development with mild dysmorphic features to early death from major malformations. This variation cannot be attributed entirely to different degrees of mosaicism.2 Two large studies have addressed the origin of trisomy 13 using microsatellites and demonstrated that the majority of cases are maternal in origin, with almost equal meiosis I and II errors as well as markedly reduced recombination.3 4 However, only two cases of mosaic trisomy 13 were included in these studies. Currently, the application of chromosome microarrays, such as oligonucleotide-based or single-nucleotide polymorphism (SNP)-based arrays, has increased the detection rate of genomic abnormalities in individuals with developmental disabilities or congenital anomalies. SNP-based arrays have the advantage of homozygosity detection, which may represent isodisomic uniparental disomy (UPD) or consanguinity. In cases with trisomy rescue, associated heterodisomic UPD can also be identified when accompanied by regions of isodisomy.5 This unique property makes SNP array particularly helpful in the determination of origin, mapping recombination sites, and direct quantification of mosaicism. In fact, a recent study using SNP array has demonstrated the feasibility of this technique in dissecting the originating mechanisms of mosaic aneuploidy and UPD as well as chimerism.6 By analysing the changes in B allele frequency (BAF) generated from genotype data in combination with the intensity data, low percentage mosaicism can be better detected and mathematically estimated.6 Not only does the timing of non-disjunction have a profound impact on embryonic development and UPD formation in the disomic line, the knowledge of whether non-disjunction originated at meiosis or mitosis also has clinical implications for predicting the risk of trisomy recurrence. Trisomy arising from maternal meiotic non-disjunction has been associated with an increased recurrence risk for a different trisomy, which indicates that some women have a higher risk of meiotic non-disjunction than others of the same age, especially in those under 35 at a previous affected pregnancy.7 8 Here we investigate the origin of three patients with mosaic trisomy 13 with varying phenotypes and cytogenetic findings. We are able to determine the timing of non-disjunction and parental origin, propose mechanistic models, and calculate the percentage of mosaicism for each case.

    Materials and methods

    Study subjects

    Three patients and their parents (both parents of patient 1, the mother of patient 2, and the father of patient 3) were studied following the guidelines of the institutional review board at the Johns Hopkins School of Medicine and the Kennedy Krieger Institute. The phenotypes of the three patients are summarised in online supplementary table S1.

    SNP array analysis

    Illumina HumanCytoSNP-12 BeadChip containing 300 000 selected markers was used in this study. Data were analysed by examining signal intensity (log R ratio) and allelic composition (BAF) with GenomeStudio V.1.1 and CNVPartition V.2.4.4.0 software. To identify the parental origin of the extra chromosome 13, the genotype data of the three patients and their parents were manually analysed. For patient 1, SNPtrio analysis was additionally performed to visualise and analyse inheritance patterns in family trios (http://pevsnerlab.kennedykrieger.org/SNPtrio.htm).9 For patients 2 and 3, SNPduo analysis was also performed to identify the relatedness between two individuals based on their identity-by-state (IBS) patterns (http://pevsnerlab.kennedykrieger.org/SNPduo/).10 Mosaicism level was calculated based on the formula for expected BAF.6

    Chromosome analysis, fluorescence in situ hybridisation (FISH) and SNP array are described in the online supplementary material.

    Results and discussion

    SNP array as an analysis tool for mosaic trisomy

    Figure 1A illustrates the outcomes of non-disjunction in maternal meiosis I (left panel), meiosis II (middle panel) and mitosis (right panel) followed by trisomy rescue, a mitotic loss of the extra chromosome. In meiosis I and II, trisomy rescue of a trisomic zygote can lead to UPD in the resulting disomic line; if there are crossovers, blocks of heterodisomy and isodisomy can then be identified from the genotype data of SNP array. Trisomies arising from meiosis I comprise three different homologous chromosomes or haplotypes, but can have two haplotypes in the crossover regions. Those arising from meiosis II contain two different haplotypes, with the addition of the third haplotype in the regions of recombination. Mitotic non-disjunction in a normal zygote (figure 1A, right panel), on the other hand, always results in two different haplotypes regardless of meiotic crossovers. Segmental UPD can also result from rare mitotic recombinations.11 In non-mosaic trisomy, BAF plots exhibit four tracks; AAA (BAF=0), AAB (BAF=0.33), ABB (BAF=0.66) and BBB (BAF=1). In mosaic trisomy, introduction of another cell line with the same haplotype or new haplotype results in a shift of the existing BAF or additional BAF tracks, respectively. In general, a four-track BAF corresponds to the various genotype combinations of two different haplotypes, while a six-track BAF plot represents those of three different haplotypes. A subtle increase in copy number represented by log R ratio between two and three copies is suggestive of trisomy mosaicism. Of note, non-disjunction in meiosis II without crossover cannot be differentiated from mitosis using BAF.

    Figure 1
    Figure 1

    Mosaic trisomy 13 associated with non-disjunction in meiosis I. (A) Simplified illustrations of the outcomes of non-disjunction followed by trisomy rescue in maternal meiosis I (left panel), meiosis II (middle panel) and mitosis (right panel); the upper rows show two recombination sites, and the lower rows show no recombination. The three possibilities of trisomy rescue and the types of uniparental disomy (UPD) in the resulting disomic line are displayed. Different colours represent different homologous chromosomes. P, paternal copy; M1, maternal copy 1; M2, maternal copy 2; hUPD-M, maternal uniparental heterodisomy; iUPD-M, maternal uniparental isodisomy. (B) Single-nucleotide polymorphism (SNP) array results of patient 1 showing the two plots, B allele frequency (BAF) and log R ratio plots consistent with mosaic trisomy 13 arising from meiosis I error with two recombination sites flanking the segmental iUPD region. The genotype combinations of the two cell lines are shown. Genotype analysis of a family trio reveals the maternal origin of non-disjunction. (C) SNP array results of patient 2 showing BAF and log R ratio plots consistent with mosaic trisomy 13 arising from meiosis I error with no recombination. Genotype analysis of patient 2 and her mother reveals the maternal origin of non-disjunction.

    Mosaic trisomy 13 associated with non-disjunction in meiosis I

    The trisomies in two of our three patients resulted from non-disjunction in meiosis I. Patient 1 is an infant with minor dysmorphic facies, failure to thrive, congenital heart defect, postaxial polydactyly and hypomelanosis of Ito. Peripheral blood karyotype showed 47 chromosomes with trisomy of chromosome 13 in 10 cells and 47 chromosomes with an extra marker in 40 cells. The marker chromosome later identified by metaphase FISH with CEP13/21 and WCP13 probes contained only the centromeric material of chromosome 13 or 21 (online supplementary figure S1). SNP array showed a six-track BAF plot, except for a region between 13q31.1 and q33.2 showing a four-track BAF (figure 1B). Copy number showed a subtle increase for the entire chromosome 13. Consistently, the genotypes of the patient and both parents analysed manually as well as with SNPtrio revealed maternal heterodisomy from centromere to genomic location 83.40 Mb (13q31.1), maternal isodisomy from 83.40 Mb to 105.63 Mb (13q31.1q33.2), and maternal heterodisomy from 105.63 Mb (13q33.2) to telomere (online supplementary figure S2A). These findings suggested the origin of trisomy 13 in maternal meiosis I with two recombination sites at 83.40 Mb and 105.63 Mb, respectively, followed by chromosome breakage and loss of paternal 13q fragment by postzygotic trisomy rescue. This also means patient 1 had segmental maternal uniparental heterodisomy/isodisomy 13 in the diploid cells, with unclear clinical significance. Although studies have indicated no parental-specific imprinting of genes on chromosome 13, the abnormal phenotypes caused by homozygosity for an autosomal recessively inherited mutation of genes on 13q should also be considered.12 13 In addition, the calculated percentage mosaicism in uncultured cells based on BAF was 40% versus 20% by cytogenetic analysis of cultured cells.

    Patient 2 is an infant who had omphalocele, mild craniofacial dysmorphism, failure to thrive, congenital heart defects and microcephaly. The neonatal karyotype was normal, but subsequent FISH follow-up with LSI13 probe demonstrated 24% trisomic interphases in the cultured peripheral blood. SNP array showed a six-track BAF plot for the entire chromosome 13, and there was only a subtle increase in copy number (figure 1C). The genotypes of the patient and the mother analysed both manually and with SNPduo showed the IBS 2 pattern, meaning the two copies of chromosome 13 were shared identically between the patient and the mother, suggesting maternal heterodisomy of chromosome 13 (online supplementary figure S2B). These results indicated that trisomy 13 originated from non-disjunction in maternal meiosis I without any recombination, followed by loss of the paternal 13 by postzygotic trisomy rescue. The calculated mosaicism level was 30%. Reduced meiotic recombination is known to predispose to non-disjunction resulting in aneuploid gametes, and is observed in other trisomies as well.14

    In addition, SNP array results compatible with those of patient 2, showing trisomy 13 originating from meiosis I with no recombination followed by postzygotic trisomic rescue, were also observed in another patient with complete mosaic trisomy 13 (data not shown).

    Mosaic trisomy 13 associated with non-disjunction in meiosis II or mitosis

    Patient 3 was the product of a diamniotic–dichorionic twin in vitro fertilisation (IVF) pregnancy; both parents have a normal karyotype. The patient was born prematurely with postaxial polydactyly, tethered cord, and mildly dysmorphic facies and is developmentally delayed. The twin brother is developmentally and karyotypically normal. Blood and fibroblast karyotypes were 45,X[25]/46,XX,der(19)t(13;19)(q14.1;q13.4)[27] and 46,XX,der(19)t(13;19)(q14.1;q13.4)[50], respectively (figure 2A, left panel). Chimerism study using microsatellites was negative. SNP array of the patient's blood for chromosome 13 showed a normal ‘three-track’ BAF (AA, AB, BB) from centromere to 13q14.11, and a four-track BAF from 13q14.11 (from 43.93 Mb) to 13qter (figure 2A, right panel). Accordingly, a subtle increase in copy number was observed from 13q14.11 to 13qter. The genotypes of the patient and the father analysed manually and with SNPduo revealed the IBS 1 pattern, which means one copy of chromosome 13 was shared between the patient and father, suggesting the maternal origin of the extra chromosome 13 (online supplementary figure S2C, left panel). Array-based mosaicism level was 40%, versus 52% by cytogenetics. In complete monosomy, a two-track BAF plot representing one haplotype is observed: AA (BAF=0) and BB (BAF=1). SNP array of the patient's blood for chromosome X showed the combination of a four-track BAF plot and decreased log R ratio (figure 2B), indicating a mosaic monosomy X with mosaicism level of 60%. SNPduo showing the IBS 1 pattern (online supplementary figure S2C, right panel) in combination with additional genotype comparisons suggested loss of the paternal X in the monosomic line. Of note, there was no loss or gain observed on chromosome 19, indicating that the translocation breakpoint was close to, or at, the telomere. We propose a model showing the origin of these two unique cell lines as illustrated in figure 2C. In brief, the non-disjunction originated in either meiosis II with no recombination or early-stage postzygotic mitotic error of a normal zygote, followed by a series of chromosome breakage, translocation and multiple anaphase lags (figure 2C, left panel). The final compositions of chromosomes 13 and X are shown in figure 2C, right panel.

    Figure 2
    Figure 2

    Mosaic trisomy 13 associated with non-disjunction in meiosis II or mitosis. (A) G-banded chromosomes of the partial trisomy 13 cell line (cell line 2) from patient 3 showing two normal chromosomes 13, a der(19)t(13;19)(q14.1;q13.4), and a normal chromosome 19 (left panel). Single-nucleotide polymorphism (SNP) array results of patient 3 showing BAF and log R ratio plots (right panel) consistent with partial mosaic trisomy 13 arising from either meiosis II with no recombination or mitotic non-disjunction. The genotype combinations of the two cell lines are shown. Genotype analysis of patient 3 and her father reveals the maternal origin of non-disjunction. (B) SNP array results of patient 3 showing BAF and log R ratio plots consistent with mosaic monosomy X arising from mitotic non-disjunction. The genotype combinations of the two cell lines are shown. Further genotype analysis reveals loss of paternal X. (C) A proposed model of the origin of the two different cell lines in patient 3 (left panel). The cell on the far left represents a trisomy 13 zygote resulting from non-disjunction in meiosis II without recombination, or a trisomy 13 cell originating from mitotic non-disjunction in the first division of normal zygote. Subsequent double chromosome breaks followed by a reciprocal translocation between 13q and subtelomeric 19q, and mitotic losses of paternal X and maternal 13 as well as maternal der(13), result in the two unique cell lines. The right panel illustrates the final combination of chromosomes 13 and X. Chromosomes 13, 19 and X are depicted in red, blue and green, respectively. P, paternal copy; M, maternal copy; M1, maternal copy 1.

    None of our three cases was associated with advanced maternal age, a known risk factor of trisomy 13.15 In addition, our findings in this group of live born patients with mosaic trisomy 13 are in line with the previous studies showing that most trisomy 13 originates in maternal meiosis with reduced recombination. Meiotic non-disjunction usually causes extensive defects in embryonic development that are not compatible with life, and mitotic error is more commonly observed in mosaic trisomies detected in live borns.16 However, this may not be true for chromosome 13, which is considered gene poor.17

    BAF-based quantification of mosaic level is a valuable tool, as it allows a direct measurement of mosaicism level from the DNA of uncultured specimens, avoiding possible selection from cultured cells. This application should be especially useful in chromosome microarray analysis of cancer samples, where heterogeneity is expected. Comparison of the calculated mosaic percentage from SNP array and the results from direct FISH preparation should help validate this promising application.

    It is not surprising that patient 3 has complex mosaic aneuploidies given that the incidence of aneuploidy in IVF embryos is higher than that observed in clinically established pregnancies, and that >50% were mosaic.18 A recent study revealed that mosaic structural chromosome abnormalities also occur at a high rate in early IVF embryos, and that mitotic non-disjunction was much more common than meiotic error, which raises questions about the frequency of cryptic mosaicism that may have important clinical implications.19 Another current report also supports the notion of somatic mosaicism as inter- and intra-individual genetic variation, emphasising the importance of mosaicism study.20

    Concluding remarks

    SNP array provides both genotype and copy number information and is useful in studying mechanisms of complex mosaic aneuploidy and UPD. Further studies may provide more insights into human mosaicism and unveil novel clinical implications.

    Acknowledgments

    We thank the members of the Kennedy Krieger cytogenetics laboratory for their excellent technical support, Dr Jonathan Pevsner for bioinformatics consultation, and the patients and families for their kind cooperation.

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    Supplementary materials

    Footnotes

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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