204 J Med Genet 1999;36:204–207 An analysis of common isodisomic regions in five J Med Genet: first published as 10.1136/jmg.36.3.204 on 1 March 1999. Downloaded from mUPD 16 probands Sayeda N Abu-Amero, Zehra Ali, Khaled K Abu-Amero, Philip Stanier, Gudrun E Moore Abstract shown to be heterodisomic for maternal UPD Intrauterine growth retardation (IUGR) for chromosome 16 (mUPD 16). with or without additional abnormalities Several mechanisms have been postulated is recognised as a common feature of for the origins of UPD. These include (1) maternal uniparental disomy for chromo- gametic complementation, for example, fertili- some 16 (mUPD 16) and is usually associ- sation of a disomic egg with a nullisomic ated with confined placental mosaicism sperm; (2) monosomic rescue, where a haploid (CPM). Although it is likely that the CPM zygote attains diploid status following mitosis; largely contributes to the IUGR, postnatal (3) somatic recombination which produces growth retardation and other common mosaicism with a normal cell line coexisting abnormalities may also be attributed to with a line with partial isodisomy; and (4) the mUPD. Five cases with mUPD 16 and trisomic rescue, where fertilisation of a disomic CPM were analysed for common regions egg by a haploid sperm produces a trisomic of isodisomy using polymorphic markers zygote. Following subsequent mitosis, loss of distributed along the length of the chro- one of the homologous chromosomes present mosome. In each case the aberration was in triplicate generates a mosaic diploid/trisomy. consistent with a maternal meiosis I error. Usually the trisomic cell line is confined to the Complete isodisomy was not detected in placenta and the fetus is diploid. In one third of any of the patients although two patients cases, the paternal chromosome is lost, leaving 56 were found to be mixed with both iso- and two copies of the maternal chromosome. heterodisomy. Interestingly, the patient The eVects of uniparental disomy become with the greater region of isodisomy was apparent when there is either exposure of a the most severely aVected. The fact that recessive gene(s) or an imprinted gene(s) on there were no common regions of isodis- the chromosome. The first case of mUPD for omy in any of the patients supports the chromosome 7 documented is that of a girl hypothesis that imprinted genes, rather with cystic fibrosis (CF) and short stature, than recessive mutations, may play a role where only the mother was heterozygous for 7 http://jmg.bmj.com/ in the shared phenotypes. the CF mutation. Since the girl showed isodi- (J Med Genet 1999;36:204–207) somy for this chromsome, that is, had inherited both copies of chromosome 7 with the mutated Keywords: IUGR; mUPD; heterodisomy; isodisomy CF allele from her mother, the recessive phenotype was exposed. In the case of imprinted genes, the unequal contribution of Intrauterine growth retardation (IUGR) is the maternal and paternal genome to the defined as birth weight below the 10th centile embryo (maternal genome contributing to the on September 30, 2021 by guest. Protected copyright. for gestational age in infants born in the same fetus, paternal genome contributing to extra- 1 community. It is one of three major causes of embryonic tissue) means that absence of the perinatal and childhood morbidity, after pre- maternal or paternal genome in pUPD or maturity and major abnormalities.2 IUGR can mUPD respectively may lead to growth and Molecular Biology result from maternal factors, such as pre- developmental abnormalities.5 Laboratory for Fetal eclampsia, fetal karyotypic chromosomal ab- The relative contributions of CPM and Development, Division normalities, and placental insuYciencies, but mUPD 16 to fetal growth retardation and par- of Paediatrics, by far the largest group is idiopathic. Obstetrics and ticularly congenital abnormalities has yet to be 3 8 Gynaecology, Imperial In 1994, Kalousek documented 73 preg- determined. CPM is associated with structural College School of nancies with IUGR or intrauterine fetal death placental abnormalities which contribute to Medicine, Queen associated with confined placental mosaicism poor fetal nutrition and blood supply, which in Charlotte’s and (CPM) (that is, the presence of two or more turn leads to growth retardation.9 Reports of Chelsea Hospital, karyotypes in placental tissue only). Chromo- CPM for chromosome 16 without associated Goldhawk Road, London W6 0XG, UK somes 2, 3, 7, 8, 9, 13, 14, 15, 16, 18, 22, and fetal mUPD for chromosome 16 indicate that S N Abu-Amero X were all associated with CPM, with trisomy the presence of high levels of trisomic cells in Z Ali 16 CPM being the most commonly associated placenta alone can produce fetal growth retar- K K Abu-Amero with IUGR (61%).3 The incidence of unipa- dation and are associated with fetal loss.10 P Stanier rental disomy (UPD; the inheritance of both However, none of these cases had associated G E Moore members of a homologous pair of chromo- malformations.8 Kalousek and Barrett11 also Correspondence to: somes from the same parent) in idiopathic reported two cases of fetal UPD for chromo- Dr Abu-Amero. IUGR with birth weights below the 5th centile some 16 with normal outcome. However, a has been reported.4 Two out of 35 were found case report ofa4yearoldpatient with mUPD Received 26 March 1998 Revised version accepted for to have CPM for chromosome 16 and also had 16 described continuing short stature as a fea- publication 17 July 1998 imperforate anus, and were subsequently ture, without any additional major cognitive Isodisomy in mUPD 16 205 eVects.12 This continued growth retardation karyotype. Case 4 was brought to our attention could be the result of either a long term eVect from a CVS showing evidence of 100% J Med Genet: first published as 10.1136/jmg.36.3.204 on 1 March 1999. Downloaded from of a compromised placenta or the continued placental trisomy for chromosome 16. The over- or underexpression of an imprinted later amniocentesis showed a normal fetal gene(s). karyotype. Polymorphic markers subsequently The five cases described here were ascer- identified mUPD 16 for both cases. Cases 3 tained through IUGR being diagnosed in utero and 4 are alive so no further analysis of mosai- or subsequent detection of trisomy 16 confined cism has been possible. Case 5, showing 53% to the placenta or both. Examination of CVS or trisomic CVS, has also previously been term placental tissue in all five cases showed reported.14 Case 5 died after 156 days and trisomy for chromosome 16 and mUPD of extensive postmortem tests were refused by the chromosome 16 in the baby. Three of the cases parents, although fibroblast cultures from two have previously been described.13 14 In this separate skin biopsies were diploid (15+30 investigation, detailed molecular characterisa- cells) and peripheral blood lymphocyte culture tion was undertaken on the five mUPD 16 was also diploid (30 cells).14 Paternity in all probands, using additional polymorphic cases was confirmed using three polymorphic VNTR probes and PCR markers to those tetranucleotide PCR markers from chromo- described previously, in order to identify some 7, D7S2846, D7S2212, and D7S1826 heterodisomic or isodisomic regions along (Research Genetics). chromosome 16 for each case. The data obtained will be useful in postulating either the DNA EXTRACTION FROM BLOOD AND PLACENTA possibility of an imprinted gene(s) on chromo- DNA was extracted from parental blood, fetal some 16 involved in growth or pockets of com- blood, and placenta as in Abu-Amero et al.15 mon isodisomy which could locate important recessive genes associated with imperforate SOUTHERN HYBRIDISATION AND RADIOLABELLED anus or heart defects. PCR Southern hybridisation and radiolabelled PCR Materials and methods were carried out as described by Abu-Amero et .16 Probes (HGMPRC) and polymorphic di- SUBJECTS al Table 1 details the medical history of the five and tetranucleotide PCR markers (HGMPRC probands investigated. Ethical approval for this and Research Genetics) were used; their project was given by the Hammersmith Hospi- cytogenetic and physical locations and in- tal Ethics Committee (94/4290) and all formativity are shown in fig 1. Polymorphic subjects gave informed consent. Cases 1 and 2 PCR markers were selected for high levels of have previously been reported by our group as heterozygosity and an even distribution along having 71% and 28% trisomic placentae chromosome 16. respectively and fetal mUPD for chromosome 16.13 Karyotyping of fetal brain, kidney, liver, Results http://jmg.bmj.com/ lung, and ovary (50 cells each) in case 1 and SOUTHERN HYBRIDISATION AND POLYMORPHIC informative polymorphic PCRs on fetal brain, PCR MARKERS kidney, liver, and lung in case 2 (unpublished Alleles for parents and probands were scored data) ruled out fetal mosaicism in these tissues according to gel mobility, and informativity for and cases.13 Case 3 was identified at birth as each probe and PCR marker is indicated in fig 1. IUGR and term placental tissue showed 100% Cases 1, 3, and 4 were heterodisomic for all trisomy for chromosome 16; a postnatal blood markers that were informative (15/18, 11/18, on September 30, 2021 by guest. Protected copyright. specimen from the baby showed a normal and 11/18 respectively). One marker (D16S7 - Table 1 Medical history of five mUPD 16 cases investigated No of trisomic cells observed/total No of cells counted Age at No of cells CVS Weight at birth counted at Placenta at Case birth (g) (wk) amniocentesis* Direct Culture