Institute of Human Genetics
Uniparental Disomy (UPD) has been observed for almost all chromosomes. In some instances, it gives rise to distinct phenotypes such as Prader-Willi, Angelman, Beckwith-Wiedemann and Silver-Russell syndrome (UPDs 15, 11, 7). UPD of some chromosomes is not associated with a clinical phenotype (UPDs 13, 21, 22) indicating that these chromosomes do not harbor imprinted genes. In most syndromes associated with UPD, pregnancy complications include intrauterine growth retardation (IUGR). This indicates that genomic imprinting plays a fundamental part in regulating antenatal growth. However, the influence of imprinting is not obligate considering that trisomic rescue is the most frequent UPD formation mechanism: trisomic rescue might lead to either placental or fetal tissue mosaicism and thereby cause a phenotype. This mosaicism may remain undetected and renders the delineation of a phenotype more difficult.
We tested a large cohort of IUGR patients with and without further clinical features for UPD of chromosomes (namely 2, 6, 9, 14, 16, and 20) the imprinting situation of which is ambiguous. The heterogeneous clinical pictures of UPDs 2, 9 and 16 and the frequently detected additional chromosomal mosaicisms suggest that placental mosaicism is the underlying mechanism causing the phenotype. Paternal UPD6 is restricted to IUGR in association with transient neonatal Diabetes mellitus and should be caused by (an) imprinted gene(s). In case of UPD14, a maternal UPD14 syndrome could be delineated which includes IUGR; an imprinting region in 14q was identified which includes the imprinted genes MEG3 and DLK1. An imprinting effect may also cause the clinical features of UPD2O since prenatally detected mosaic trisomy 20 does usually not affect the pregnancy outcome.
In conclusion, most of the known UPDs with clinical abnormalities can be divided in two groups: the ones belonging to imprinting syndromes and the ones caused by placental dysfunction as the result of a chromosomal aberration. Both groups include growth abnormalities and some more or less specific clinical features. However, there remain UPDs such as maternal UPD7 in Silver-Russell syndrome in which both imprinting and chromosomal aberrations appear to influence the phenotype. Whether pre-eclampsia as a further general pregnancy complication is influenced by imprinting as it may be assumed by the nature of the disease, remains to be elucidated.