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Review Article J Med Genet: First Published As 10.1136/Jmg.31.8.585 on 1 August 1994

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Review Article J Med Genet: First Published As 10.1136/Jmg.31.8.585 on 1 August 1994 J Med Genet 1994;31:585-594 585 Review article J Med Genet: first published as 10.1136/jmg.31.8.585 on 1 August 1994. Downloaded from Inv dup(15) supernumerary marker chromosomes Tessa Webb In the course of cytogenetic studies, the detec- euchromatin present in the marker very diffi- tion of a supernumerary additional small cult. Robinson et aP have shown by molecular marker chromosome is not an uncommon methods that clinical severity can be related to occurrence. In lymphocytes the presence of gene dosage rather than to the actual physical such a marker, once identified, may be directly size of the marker chromosome. The majority correlated with the clinical phenotype but in of inv dup(15) chromosomes reported have prenatal samples such as CVS or amniocytes two distinct centromeres with an area of euch- there are often difficulties in interpretation. romatin lying between them, but in many cases These difficulties not only involve the identi- one of the centromeres appears to be inactive, fication of the chromatin fragment from which giving the dicentric marker the appearance of the additional material has been derived but an acrocentric chromosome. also the prediction of its likely effect upon the One interesting aspect of the presence of an phenotype. additional marker chromosome derived from The first problem is gradually being over- proximal 15q is its occasional occurrence in come with the advent of fluorescence in situ conjunction with Prader-Willi syndrome hybridisation (FISH) which has the ability to (PWS). Prader-Willi syndrome is generally as- identify chromatin material selectively by sociated with a loss of material in proximal 15q using chromosome specific libraries. The diffi- rather than a gain. Approximately 75% of culty in relating marker to phenotype will only patients with PWS have a paternally derived become resolvable by defining not only the deletion in 15qI l-q134 while the greater major- original location of the extra material but also ity of the remaining probands have maternal how much excess euchromatin is actually pres- uniparental disomy (UPD) of chromosome 15.5 ent. Although in these cases there is no actual loss of One of the most common chromosome chromosome 15 material, the maternal copy of markers is the inv dup(15) or idic(15), which the PWS critical region is believed to be http://jmg.bmj.com/ may represent as many as 50% of the small imprinted and non-functional.6 Angelman syn- supernumerary chromosomes detected during drome has only very rarely been associated with routine karyotyping. Buckton et all in their the presence of a supernumerary marker chro- study of 44 marker chromosomes found an inv mosome derived from proximal 15, despite the dup(15) to account for 17 of those detected. In finding that the majority of cases also have a a survey of 16 395 newborn babies they found deletion in 15qllql3.7 In this syndrome, the an incidence of supernumerary markers of0-24 deletion occurs on the maternally derived on September 24, 2021 by guest. Protected copyright. per 1000. Among 1142 persons with congenital homologue of chromosome 15,8 and occasion- abnormalities, however, the incidence was 10 ally paternal UPD of the chromosome has also times higher at 2-63 per 1000. In another study been observed.9 of 5049 newborn babies, 0-06% were found to A study of published reports indicates that carry markers, of which 33/64 were inv there have been more than 50 published obser- dup(15).2 vations of probands with a supernumerary The phenotype of probands who carry such marker chromosome inv dup(15) or idic(15). a marker varies considerably from apparently The clinical phenotype and the reported size of unaffected persons to those who are severely the marker chromosome are so variable that it mentally retarded. Correlations have been was decided to investigate the possibility of attempted between the severity of the pheno- classifying the marker chromosomes into type and the size of the additional marker groups according to their size and appearance chromosome but the degree of polymorphism and then to correlate this with phenotype. associated with proximal chromosome 15 There are several different methods used to makes accurate estimation of the amount of indicate the size and type of any particular marker chromosome. Where photographs are published and comparisons made with these descriptions, it appears that despite these vari- The earliest papers describing a supernumerary inv dup(1 5) ations, the markers can be divided into groups Department of tended to refer to a "marker" or an "SBAC" (small bisatellited Clinical Genetics, acrocentric chromosome) and are included in this review if the as follows. Birmingham marker is distamycin/DAPI positive. In later work, the term Group 1: small inv dup(15) markers. This Maternity Hospital, "inv dup (15)" predominates, even though at one point "idic group includes all those markers with appar- Edgbaston, (15)" was considered to be more accurate, and is the term favoured by ISCN (1985). Although in the papers quoted either ently one centromere caused by close proxim- Birmingham term is encountered, for the sake of clarity and because the later B15 2TG, UK molecular papers all quote "inv dup(15)" this term has been used ity of the two pericentromeric regions. It also T Webb throughout. includes markers with two distinct centro- 586 Webb meres but described as being smaller than a G only the patient ascertained from a survey of group chromosome and also those classified as mental hospitals' was found to be mentally belonging to the AI group as delineated by retarded with dysmorphic features. This type J Med Genet: first published as 10.1136/jmg.31.8.585 on 1 August 1994. Downloaded from Steinbach et al.10 Still others were described as ofmarker is sometimes fortuitously detected in metacentric, or having breakpoints in 15qi 1. amniotic fluid or CVS samples, or through Group 2: medium sized inv dup(15) population surveys, while two of the probands markers. This group all had two distinct cen- were detected during surveys of secure institu- tromeres with some visible chromatin between tions.1 them. They were often also defined as the same Group 2: markers containing extra material size as a G group chromosome or as belonging from pter-qI2. Table 2 summarises reports of to type All in the Steinbach et al'° classifica- medium sized supernumerary inv dup(15) tion. Often they were referred to as submeta- chromosomes classified into group 2. Ascer- centric or sometimes even acrocentric in type. tainment in 25/37 cases was a consequence of The breakpoints in these markers tended to lie mental retardation or developmental delay. in 15ql2. As one of the two centromeres is Other reasons for ascertainment included aut- usually inactive, this marker chromosome ism27 and a case of neuroleptic malignant syn- sometimes has the appearance of a small sub- drome.29 One subject was found in the course metacentric chromosome.11 of a newborn survey1 and a further four were Group 3: large inv dup(15) markers. These detected during prenatal diagnosis.2530 Only also have two separate centromeres which may seven out of 36 persons were mentally normal have distinct banding observable between and some mental handicap was reported as them. The group also includes markers de- severe or even profound. Many of the pro- scribed as being larger than a G group chro- bands had behavioural problems or seizures or mosome and those falling into type AIII in the both and several had an abnormal EEG (table Steinbach et al'0 classification. This type of 3). Among the seven subjects who were not marker was often described as acrocentric or described as having mental retardation or de- like an acrocentric chromosome, and the velopmental delay, two were ascertained breakpoints lie in 15q13 or in a more telomeric through a survey of newborns and a third was band of chromosome 15. the unaffected mother of a girl with Turner's Further classification was needed to de- syndrome. This latter marker was however scribe situations which did not fall simply into familial and maternally derived (table 3). One one of these three categories. These included further subject with normal intelligence was familial or inherited markers and the rare from a maximum security hospital.' occurrence of more than one marker in a single Obesity was not a feature of these probands person. In addition, cases of PWS and the and neither was hypogonadism, and approx- chance finding of supernumerary inv dup(15) imately half of them were without physical in the course of prenatal diagnosis were also stigmata. considered independently, as was the presence Group 3: large inv dup(15) markers contain- http://jmg.bmj.com/ of the marker in mosaic form. ing material from l5pter-q13. Table 4 sum- Group 1: markers which only contain extra marises reports of supernumerary inv dup(15) material from pter-ql 1. Table 1 contains a chromosomes classified into group 3. Ascer- summary of reports describing group I or tainment in almost all cases was by mental small supernumerary inv dup(15). Of the 12 retardation or developmental delay. probands recorded, mental retardation or de- This third group of inv dup(15) marker chro- velopmental delay was present in only five, mosomes contains all those described as larger on September 24, 2021 by guest. Protected copyright. while the other seven were stated to be men- than a G group chromosome. They are often tally normal. There was a marked absence of seen as acrocentric rather than dicentric and the other clinical findings in this group. There breakpoints are at ql3:ql3 or even in one case were four cases of PWS with the clinical signs q14:q14 (table 4).
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