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Maternal uniparental disomy 12 in a healthy girl with a 47,XX,+der(12)(:p11→q11:)/46,XX karyotype
  1. F von Eggeling1,
  2. C Hoppe1,
  3. U Bartz2,
  4. H Starke1,
  5. G Houge3,
  6. U Claussen1,
  7. G Ernst1,
  8. D Kotzot4,
  9. T Liehr1
  1. 1Institute of Human Genetics and Anthropology, University of Jena, Jena, Germany
  2. 2Private Practice in Gynaecology and Obstetrics, Berlin, Germany
  3. 3Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  4. 4Institute of Human Genetics, Technical University Munich, Munich, Germany
  1. Correspondence to:
 Dr F von Eggeling, Institut für Humangenetik und Anthropologie, Klinikum der FSU Jena, 07740 Jena, Germany;

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Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent, either as both homologues (heterodisomy), as two copies of one homologue (isodisomy), or as a mixture of heterodisomic and isodisomic segments. So far, UPD of whole chromosomes has been described in different clinical cases for most of the human chromosomes, except for maternal UPD(3), (5), (11), (12), (18), and (19) and paternal UPD(3), (4), (9), (12), (17), (18), and (19).1,2 Problems associated with UPD include trisomy mosaicism, homozygosity of autosomal recessively inherited mutations, and genomic imprinting. The latter describes the epigenetic phenomenon of a parental origin dependent gene expression. Cases with complete or segmental UPD might be helpful in mapping rare autosomal recessive disorders or chromosomal regions of genomic imprinting. We report here the first case of maternal uniparental disomy 12 in a healthy girl.


Amniocentesis was performed, because of advanced maternal age, in the 19th week of gestation in a 45 year old gravida 1, para 0 woman. Cytogenetic analysis using standard procedures showed a supernumerary marker chromosome (SMC, fig 1A) in 16 of 30 metaphase spreads (karyotype 47,XX,+mar [16]/46,XX [14]). The SMC was further characterised by centromere specific multicolour fluorescence in situ hybridisation (cenM-FISH)3 and, because several cases of SMC and UPD have been published,4 molecular analysis was undertaken.

Figure 1

Images were captured on a Zeiss Axioplan microscope (Zeiss Jena, Germany) with the IKAROS and ISIS digital FISH imaging systems (MetaSystems, Altlussheim, Germany) using an XC77 CCD camera with on chip integration (Sony). (A) Partial GTG banded metaphase from amniocytes of the proband. Karyotype 47,XX,+mar. The SMC is marked with an arrowhead. (B) CenM-FISH results from the proband; the SMC is identified as a der(12). Five different fluorochromes plus DAPI counterstain were used and are overlaid in this figure. To clarify which fluorochrome combination has been used for each chromosome and its centromeric region, the corresponding fluorochromes are shown in the row of squares below each chromosome pair. (C) Verification of cenM-FISH results using single colour FISH with a commercially available centromeric probe for chromosome 12 (Vysis, Germany). (D) Whole and partial chromosome painting probes for chromosome 12 (wcp 12 and pcp12p) stained the two chromosomes 12 as expected, and gave no specific signals on the derivative chromosome (arrowhead).

The pregnancy was unremarkable and a girl was born after 39 weeks of gestation. Birth weight was 2850 g, length was 46 cm, and occipital head circumference was 34 cm, all around the 50th centile. Apgar scores were 9 at one minute and 10 at five minutes. All routine postnatal investigations gave normal results. No congenital anomalies or dysmorphic features were noted. At the age of 6 weeks, clinical examination indicated normal somatic and psychomotor development. Owing to the unremarkable clinical course, no further diagnostic procedures have been performed so far.


For UPD analysis, genomic DNA was extracted from peripheral lymphocytes of both parents and from amniocytes of the fetus using standard procedures. Sequence information and chromosomal locations of all markers (table 1) are available from the National Center for Biotechnology Information (NCBI) or the Genome Database (GDB).5,6 Twenty-five cycles of PCR were performed with infrared labelled primers (IRD800, MWG-Biotech, Germany). Denatured samples were loaded onto a 6% denaturing polyacrylamide gel, separated electrophoretically on a Licor DNA 4000 sequencer (LI-COR, Neb), and detected with an infrared laser diode.

Table 1

Results of microsatellite analysis of chromosome 12 in the proband and her parents

Molecular-cytogenetic investigations with cenM-FISH and chromosome painting probes were performed as described elsewhere.3,7


Using centromere specific multicolour fluorescence in situ hybridisation (cenM-FISH), the SMC was identified as deriving from the centromeric material of chromosome 12 (fig 1B, C). Interphase FISH using centrimeric probe 12 exclusively identified the SMC in 74 of 150 nuclei. Molecular-cytogenetic investigations with chromosome painting probes for the whole of chromosome 12, in combination with a short arm probe for chromosome 12, labelled in two different colours, produced no positive signal (fig 1D). Both parents displayed normal karyotypes in peripheral blood. The father, in particular, displayed no SMC in 50 metaphase spreads and 200 interphase cells. In the mother, 20 metaphase spreads and 200 interphase cells showed an unremarkable 46,XX karyotype.

For UPD analysis, 17 highly polymorphic microsatellite markers mapped to chromosome 12 were investigated. Only maternal alleles were detected at six loci (table 1). Three microsatellites indicated heterodisomy (D12S373, D12S1042 (fig 2), and D12S375), and two markers showed isodisomy (D12S395 and D12S2078 (fig 2). For one microsatellite (D12S100), both the mother and the proband were homozygous for the same allele, whereas the father was homozygous for a different allele (fig 2). At 11 loci, patterns non-informative for UPD were found, but the results from all these markers were consistent with maternal UPD(12). From these results, we inferred maternal UPD of the whole of chromosome 12. Of the 11 markers that were non-informative for UPD, heterodisomy was noted in three markers (D12S372 (fig 2), D12S1052, and D12S1064) and isodisomy also in three markers (D12S398, D12S2070, and D12S1045). Data from the investigation of six highly polymorphic markers located on two other chromosomes excluded non-paternity as well as maternal contamination of the amniocyte cultures.

Figure 2

Results of microsatellite analysis for D12S1042, D12S2078, D12S100, and D12S372 in the mother (M), the father (F), and the proband (P). Different alleles are labelled a, b, and c. Maternal heterodisomy is apparent for D12S1042 and maternal isodisomy for D12S2078. D12S100 is shown to exemplify a non-informative maternal UPD; the mother and the proband are both homozygous for aa, with no paternal allele in the proband. D12S372 exemplifies a non-informative allele, which is, however, consistent with the assumption of complete maternal heterodisomic UPD.


The combination of a minimum of two heterodisomic segments and two isodisomic segments is most easily explained by one recombination between D12S1042 and D12S398, one recombination between D12S398 and D12S375, and one recombination between D12S1064 and D12S2070. Additional recombination events cannot be excluded because of the genetic distance between the loci (on average about 10 cM). Heterozygosity at marker D12S1042, which has been mapped very close to the centromere, strongly suggests a segregation error at maternal meiosis I.

Heterodisomy and chromosomal mosaicism indicate the formation of the 46,XX cell line by trisomy rescue. At the time of fertilisation, the SMC was either already present in the paternal gamete or there were three chromosomes 12 in the zygote, and the SMC was formed at a subsequent mitosis by two breaks both localised next to the centromere. The coming together of two maternal chromosomes 12 and a functionally irrelevant marker chromosome allowed the survival of the fetus.

The clinically relevant problems that are associated with UPD include trisomy mosaicism, homozygosity of autosomal recessive mutations, and genomic imprinting. Chromosomal mosaicism is present, but both the FISH results and the nor-mal clinical phenotype indicate that the marker contains only heterochromatic or phenotypically irrelevant genetic material. Homozygosity for an autosomal recessive mutation cannot be excluded, but no clinical symptoms have been observed to date. The same holds true for genomic imprinting effects. Furthermore, no genomic imprinting has been described for homologous segments in the mouse model.8 Human chromosome 12 is homologous to mouse chromosome 10 and, in smaller parts, to the central regions of chromosomes 2, 3, 5, 6, and 15.9 Therefore, despite the young age of the child, her normal somatic and psychomotor development makes one or a combination of these complications very unlikely.

In conclusion, our results indicate that maternal UPD(12) is associated with a normal phenotype if neither mosaicism of euchromatic material nor homozygous recessive mutations are present.