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A Fetus with an X;1 Balanced Reciprocal Translocation and Eye

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A Fetus with an X;1 Balanced Reciprocal Translocation and Eye I Med Genet 1995;32:557-560 557 A fetus with an X; 1 balanced reciprocal translocation and eye disease J Med Genet: first published as 10.1136/jmg.32.7.557 on 1 July 1995. Downloaded from Mary J Seller, Kalyani Pal, Sharon Horsley, Angela F Davies, A Caroline Berry, R Meredith, Alison C E McCartney Abstract changes consistent with the early stages ofNor- A 19 week female fetus is described with a rie disease. de novo X;1 reciprocal balanced trans- location, with the breakpoint on the X chromosome at Xpll.4, and eye pathology Case report consistent with the early stages of Norrie This was the sixth pregnancy of a healthy white disease. The fetus seems to be an example couple aged 37 and 41 years. The previous of a female manifesting an X linked re- children, five boys and one girl, are well, in- cessive disease, and it was shown that the cluding a boy, one of twins and now 13 years normal X chromosome was completely old, who had surgery during infancy for trans- inactivated in all cells examined. Norrie position ofthe great vessels. The family history disease has been mapped to Xpll.3, and did not indicate anything significant except for fluorescence in situ hybridisation studies a niece on the paternal side who had multiple showed that the Norrie disease gene had abnormalities and died. No precise diagnosis not obviously been disrupted. Mutation had been made but a chromosome abnormality screening by SSCP analysis showed no was suspected. For this reason, and on grounds aberrant fragments of the coding region of maternal age, chorionic villus sampling was ofthe gene. Several eye disease genes map performed in the 11th week of pregnancy. The to the same region of the X chromosome, chromosome complement from both direct and but are excluded on grounds ofpathology. cultured preparations showed a female fetus One possibility is that this fetus has a with a balanced reciprocal translocation be- Norrie-like eye disease caused by the tween the X chromosome and chromosome 1. mutation of another gene located at In view ofthis unexpected finding, and because Xpll.4. Ifthis is so, there are implications the tissue sample had been very small and for prenatal diagnosis. obtained from a single site, an amniocentesis was subsequently performed. The chromo- (JMed Genet 1995;32:557-560) some abnormality was confirmed. Both par- http://jmg.bmj.com/ ents had normal karyotypes, so the fetus ap- peared to have a de novo translocation: 46,X, Genes for a number of eye diseases are located t(X;1)(pl1.4;p36.3). The parents were in- on the X chromosome and several, such as formed that, since the X chromosome was Norrie disease, retinitis pigmentosa type 2, involved, there was some risk of a mental or cone dystrophy, congenital night blindness, and physical abnormality in the child, and because Aland Island eye syndrome, map to the same the gene for Norrie disease has been mapped on September 26, 2021 by guest. Protected copyright. region of the short arm.' One of these, Norrie to the area of the X chromosome involved in South East Thames disease, has been well characterised. the translocation, there was the possibility that Regional Genetics In Norrie disease, blindness is often present this gene might have been disrupted. The par- Centre, 8th Floor from and a of patients later ents termination of the Guy's Hospital Tower, birth, proportion requested pregnancy. Guy's Hospital, develop mental retardation, psychotic be- The female fetus was of a size and stage of London SE1 9RT, UK haviour, and sensorineural deafness.' Linkage development consistent with its gestational age M J Seller analysis and deletion mapping led to the gene of 19 weeks. There was mild ocular hy- K Pal S Horsley being localised to the region of Xpll.3.?- A pertelorism and small, low set ears. The right A F Davies candidate gene was isolated by positional lung had only two lobes, but the fetus was A C Berry cloning, within which mutations have been otherwise grossly normal except for the eyes. Cytogenetics Services, identified in affected, but not in normal, 48 Wimpole Street, people.67 Despite this, chromosomal studies London WlM 7DG, on a family with affected subjects and an X Pathology of the eyes UK R Meredith chromosome rearrangement suggested that the Both eyes were clearly abnormal (fig 1). On gene was located around Xp 1 4.8 The gene macroscopic examination, the right eye showed Division of product has significant homologies to a number an organised retrolenticular fibrotic mass with Histopathology, St Thomas's Hospital, of extracellular proteins,9 and three di- the vessels being ensheathed in a denser mass London SE1 7EH, UK mensional modelling shows a similarity to of fibrous tissue filling the vitreous and causing A C E McCartney transforming growth factor 1.10 focal detachment of the retina. The left eye Correspondence to: We describe a fetus found at prenatal diag- was similar, but less severely affected. It showed Dr Seller. nosis to have a de novo balanced X; 1 reciprocal a mass of vessels persisting in the vitreous Received 25 February 1994 translocation in whom, following termination forming a conical postlenticular mass, from Revised version accepted for publication of pregnancy at 19 weeks, the eyes were clearly which there had been small focal haemorrhages. 27 February 1995 abnormal and appeared to show pathological The leash of vessels was associated with an 558 Seller, Pal, Horsley, Davies, Berry, Meredith, McCartney each showed the abnormal karyotype with the breakpoint on the X chromosome clearly at p11.4. X inactivation studies were performed on fibroblast cells using 5-bromodeoxyuridine J Med Genet: first published as 10.1136/jmg.32.7.557 on 1 July 1995. Downloaded from (BrdU) incorporation, followed by staining with Hoechst 33258 in the dark, then ultra- violet light exposure, and final staining with Leishman's. Since this method uses a B pulse of BrdU, late replicating regions appear pale. In all 43 metaphases studied, the normal X chromosome was the late replicating chro- mosome. This normal X was consistently pale throughout its length and so was considered to be completely inactivated. Neither of the translocated products showed any evidence of late replication. In particular, the derived X was always dark staining and so appeared to be the active X chromosome in every cell examined. DNA probes and in situ hybridisation Chromosomal fluorescence in situ hy- bridisation (FISH) analysis was performed to determine whether the translocation disrupted the Norrie disease gene. Purified DNA from three cosmid clones, M8, G8, and Al0 which cover the entire Norrie disease gene region (kindly supplied by Dr Wolfgang Berger, Human Genetics Department, University Hospital, Nijmegen, The Netherlands), were labelled with biotin by nick translation (Bio Nick Labelling System, BRL Life Tech- nologies, USA) and used individually as FISH probes on metaphase chromosomes." Hy- bridisation was carried out for 16 hours at 37°C, and signals were developed with fluor- http://jmg.bmj.com/ escein labelled avidin and biotinylated anti- avidin. The slides were mounted in antifading medium containing DAPI as counterstain, and Figure 1 Macroscopic appearance of a transverse section of (above) right eye and (below) left eye, showing an organised retrolenticularfibrotic mass more marked in the viewed using a cooled CCD camera and image right eye than the left. analysis system (Digital Scientific Ltd, UK). G banding was enhanced using the Smartcapture software. organising delicate fibrous membrane. Mi- Each of the three cosmids, Al0, G8, and on September 26, 2021 by guest. Protected copyright. the presence of a croscopically, persistent prim- M8, hybridised to the normal X chromosome ary hyperplastic vitreous in both eyes was at Xp 11.3. The three cosmids also hybridised confirmed, arising as a result of the prolonged to the translocated X proximal to the break- presence of the hyaloid artery within the eyes point. No hybridisation signals were seen on and the subsequent development of a fibro- the derived chromosome 1 (fig 2). This would vascular membrane. In the retinas there were suggest that the Norrie gene is intact in this some artefactual Lange's folds, but no evidence patient. of true retinal dysplasia. As appropriate for 19 weeks gestation, photoreceptor formation was not complete and active cell division and neuroblastic activity was present. There was Mutation screening thus no evidence of a primary neuroectodermal DNA was prepared from cultured fibroblasts defect at this stage. It was considered that the by standard methods and mutation screening postlenticular masses observed were capable of by single strand conformation polymorphism evolving into an organised vitreous which (SSCP) analysis was kindly performed by Do- would have resulted in retinal traction and rien Van de Pol (Human Genetics Department, detachment. The findings thus appeared to University Hospital, Nijmegen, The Neth- be consistent with the early stages of Norrie erlands). No aberrant fragments for the coding disease. part of the Norrie disease gene were detected, suggesting that there is no mutation in this region in this fetus, although it does not com- Cytogenetic studies pletely exclude the possibility of a mutation Blood, umbilical cord, spleen, ovary, and skin there, or of a mutation elsewhere in the gene from the fetus were cultured separately, and outside the open reading frame. A fetus with an X;1 balanced reciprocal translocation and eye disease 559 excluded that the breakpoint was within the most distal part of exon 3, because that region lies approximately 20 kb from the distal end of cosmid M8, and so a hybridisation signal would AW - have been expected to be visible on the derived J Med Genet: first published as 10.1136/jmg.32.7.557 on 1 July 1995.
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