Small supernumerary marker chromosomes - Semantic Scholar

Original Article Cytogenet Genome Res 107:55–67 (2004) DOI: 10.1159/000079572

Small supernumerary marker chromosomes (sSMC) in humans T. Liehr, U. Claussen, and H. Starke Institute of Human Genetics and Anthropology, Jena (Germany)

Abstract. Small supernumerary marker chromosomes (sSMC), defined as additional centric chromosome fragments too small to be identified or characterized unambiguously by banding cytogenetics alone, are present in 0.043 % of newborn children. Several attempts have been made to correlate certain sSMC with a specific clinical picture, resulting in the description of several syndromes such as the i(18p)-, der(22)-, i(12p)(Pallister Killian syndrome) and inv dup(22)- (cat-eye) syndromes. However, most of the remaining sSMC including minute-, ring-, inverted-duplication- as well as complex-rearranged chromosomes, have not yet been correlated with clinical syndromes, mostly due to problems in their comprehensive char-

Overview on sSMC The report most often cited as the first description of a small supernumerary marker chromosome (sSMC; the abbreviation sSMC is used throughout this review irrespective if we talk of one small supernumerary marker chromosome or of two or more marker chromosomes) is Froland et al. (1963). However, this was in fact the third sSMC case, preceded by Ellis and coworkers (1962) who reported “an aberrant small acrocentric chromosome”, and Ilberry and coworkers (1961). A clear definition of sSMC is conspicuously lacking throughout the corresponding literature. Crolla proposed a “minimal definition” for sSMC as “small structurally abnormal

Supported by the Dr. Robert Pfleger-Stiftung. Received 29 March 2004; manuscript accepted 18 May 2004. Request reprints from Dr. Thomas Liehr, Institut für Humangenetik Postfach, DE–07740 Jena (Germany); telephone: +49 3641 935533 fax: +49 3641 935502; e-mail: [email protected]

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acterization. Here we present an overview of sSMC, including the first attempt to address problems of nomenclature and their modes of formation, problems connected with mosaicism plus familial occurrence. The review also discusses the frequency of sSMC in prenatal, postnatal, and clinical cases, their chromosomal origin and their association with uniparental disomy. A short review of the up-to-date approaches available for sSMC characterization is included. Clinically relevant correlations concerning the presence of a specific sSMC and its phenotypic consequences should become available soon. Copyright © 2004 S. Karger AG, Basel

chromosomes that occur in addition to the normal 46 chromosomes” (Crolla et al., 1997). Part of the problem is that the phenotypes associated with sSMC are hugely variable, from normal to severely abnormal (Paoloni-Giacobino et al., 1998). Prenatally ascertained cases with small markers which have arisen de novo are particularly difficult to associate with a clinical outcome. The correlation of specific sSMC with distinct clinical pictures has been possible for some syndromes, for example the i(18p) syndrome, i(12p)- (Pallister-Killian) syndrome, der(22)and cat-eye syndromes (Crolla, 1998). In general, the risk for an abnormal phenotype in prenatally ascertained de novo cases with sSMC is given as F13 % (Warburton, 1991); i.e. 7 % for sSMC from chromosomes 13, 14, 21 or 22 and 28 % for nonacrocentric chromosomes (Crolla, 1998). In summary, 1,528 cases with sSMC characterized by molecular cytogenetic methods for their chromosomal origin were included in this review; 1,396 of those cases had at least 47 chromosomes, the remaining 132 had 46 chromosomes and a Turner syndrome-like appearance. Additionally, for the reviewed data on sSMC frequencies in different populations, 427 sSMC cases of unknown chromosomal origin were included. An sSMC not characterizable by fluorescence in situ hybridiza-

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tion (FISH) described by Mackie Ogilvie et al. (2001) and sSMC detected in tumor cytogenetics were not included in this review.

Nomenclature and definition of sSMC Nomenclature of sSMC sSMC were given various names throughout the last decades. The three best known are: “SMC”, which does not distinguish between larger and smaller supernumerary marker chromosomes (e.g. Crolla, 1998), extra structurally abnormal chromosome (= ESAC; e.g. Hook and Cross, 1987) and supernumerary ring chromosome (= SRC; e.g. Blennow et al., 1994). It is stated that SRC constitute about 10 % of SMC (Blennow et al., 1994). In addition, the following names can be found: accessory chromosome (= AC; Soudek and Sroka, 1977; or ACH; Soudek et al., 1973), small accessory chromosome (= SAC; Vermeesch et al., 1999), marker chromosome (Nielsen and Rasmussen, 1975), extra or additional marker chromosome (Buckton et al., 1985; Martin et al., 1986), supernumerary or extra microchromosome (Howard-Peebles, 1979; Chudley et al., 1983), additional or metacentric chromosome fragment (Den Dulk et al., 1966), (centric) fragment (Hoehn et al., 1970), or small bisatellited additional chromosome (= SBAC; Mattei et al., 1984). The ISCN defines “marker” chromosome as “an abnormal chromosome in which no part can be identified” (ISCN, 1995). However, sSMC are often incorrectly described thus: “a SMC/ ESAC/marker chromosome derived from chromosome 1 was identified” (Callen et al., 1999). Definition of sSMC sSMC are a morphologically heterogeneous group of structurally abnormal chromosomes: different types of inverted duplicated chromosomes, minute chromosomes and ring chromosomes can be detected (see Fig. 1). Thus, the description of sSMC as “markers”, makes sense and should be maintained, even after their identification by molecular cytogenetics. A short definition of sSMC is not easy, and we suggest for the first time a cytogenetic one as follows: sSMC are structurally abnormal chromosomes that cannot be identified or characterized unambiguously by conventional banding cytogenetics alone, and are (in general) equal in size or smaller than a chromosome 20 of the same metaphase spread (see Fig. 1). sSMC can be present additionally (1) in a karyotype of 46 normal chromosomes, (2) in a numerically abnormal karyotype (like Turner or Down syndrome) or (3) in a structurally abnormal but balanced karyotype (e.g. Robertsonian translocation; Wolff and Schwartz, 1992) or ring chromosome formation (e.g. Lasan Trcic et al., 2003). In contrast, a SMC larger than chromosome 20 usually can be identified based on chromosome banding. Thus, cases with i(9p) are not included in the group of sSMC in this review, as previously done (see e.g. Viersbach et al., 1998). The definition of small SMC versus large(r) SMC is a cytogenetic, not a “functional” one, i.e. sSMC and larger SMC can have the same modes of karyotypic evolution (see below).

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Cytogenet Genome Res 107:55–67 (2004)

sSMC formation Different mechanisms of sSMC formation including trisomic rescue, monosomic rescue, post fertilization errors and gamete complementation have been proposed in the literature (Bartels et al., 2003). Mosaicism resulting in one cell line with sSMC and one with a trisomy provided evidence for functional trisomic rescue as a really existing mechanism (Bartels et al., 2003). Recently, a new mechanism was proposed, in which sSMC originated from transfection of chromosomes into the zygote derived from one or more superfluous haploid pronuclei that would normally be degraded by deoxyribonucleases or other means (Daniel and Malafiej, 2003). This provides a possible explanation for the formation of multiple sSMC of different origin. Inverted duplication chromosomes Several modes of formation for inverted duplication (acrocentric) chromosomes (see Fig. 1) have been proposed (Schreck et al., 1977; Ing et al., 1987; Narahara et al., 1992). The most plausible of these is a U-type exchange resulting from crossover mistakes of chromatids of two homologous chromosomes during meiosis (Schreck et al., 1977; see Fig. 2c). A U-type exchange is also proposed for the formation of isochromosomes of non-acrocentric chromosomes this time with a break within the centromeric DNA (Dewald, 1983). This is a more general mechanism of isochromosome formation present not only in germ cells, but also in tumor cells (Mukherjee et al., 1991). Neocentric chromosomes In recent years, an increasing number of supernumerary human marker chromosomes have been reported with centromeres that contain no detectable alpha-satellite DNA. These so-called analphoid markers “carry newly derived centromeres (or ‘neocentromeres’) that are apparently formed within interstitial chromosomal sites that have not previously been known to express centromere function” (Choo, 1997). The development of the majority of neocentric sSMC is based on a U-type exchange (see Fig. 2c; Voullaire et al., 2001). Most of the neocentric sSMC included in this review (see Fig. 3) are small isochromosomes. The acentric fragment created during an U-type exchange in these cases is included into a gamete, a neo-centromere is activated and the new chromosome (-fragment) is distributed throughout further cell cycles. This theory is supported by the fact that the frequency of inv dup(15) chromosomes is similar to that observed in neocentric chromosomes 15 among other acrocentric derived chromosomes of the corresponding groups. As shown in Fig. 3, 11 of the 18 cases derived from acrocentrics (i.e. F60 %) are derived from chromosome 15. About half of the cases summarized in Fig. 4 are centric acrocentric sSMC, thus also F60 % of this group are inv dup(15) cases. For all neocentric sSMC(1) (Slater et al., 1999; Spiegel et al., 2003), sSMC(2) (Choo, 1997) and sSMC(4) (Grimbacher et al., 1999) as well as for one neocentric sSMC(13) (Knegt et al., 2003), a ring chromosome conformation is described. The mechanism for ring chromosome formation shown in Fig. 2a

inv dup

r

del

min

}

} }

#20

r

r

del

idic

1

meiotic division

prophase 1 synapsis

2a

2b

OR

replication

U-type exchange meiosis NEO centromerization replication

2c 12 sSMC cases with neo-centromeres 10 8 6

min ring inv dup ring

4

2d

2e

#18

#17

#16

#14

#7

#11

#5

#4

#2

#12

#9

#10

#1

#8

#3

#13

0

#15

2

3

Fig. 1. Small supernumerary marker chromosomes (sSMC) can have different forms; they can appear as inverted duplication chromosomes (inv dup), minute chromosomes (min) or ring chromosomes (r). We define sSMC as small structurally abnormal chromosomes, in general equal in size or smaller than a chromosome 20 of the same metaphase spread, as larger SMC can usually be characterized by banding cytogenetics. Fig. 2. The postulated different modes of sSMC formation are summarized here. Ring chromosome formation can be (a) due to an interstitial deletion, (b) arise connected with a complex chromosomal rearrangement leading to an inverted duplication prior to the formation of a ring, (d) in connection with a U-shape reunion between broken sister chromatids leading to an inverted duplicated ring or (e) evolve from a minute chromosome. The latter is postulated to evolve by degradation of a whole chromosome, which is indicated by the red arrows in the left part in e. (c) Development of an acrocentric inverted duplication chromosome; for non-acrocentric iso-chromosomes the same U-type exchange during meiosis is thought to be the most likely explanation for sSMC formation, as well. In the lower part of c, the evolution of a neocentric chromosome in connection with a U-type exchange is depicted. Fig. 3. 47 cases with neocentric sSMC are reported in the literature. Their distribution according to the chromosomal origin is shown here.


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appeared in the aforementioned cases: a part of the chromosome is excised by unknown mechanisms and for unknown reasons and a neocentric chromosome is built, while the original centromere stays at the shortened chromosome (Schuffenhauer et al., 1996). Small supernumerary ring chromosomes (sSRC) Several possible explanations for formation of non-neocentric small supernumerary ring chromosomes (sSRC) are available. Firstly, sSRC can be formed in association with a deletion of a part of the chromosome; in contrast to neocentric sSMC, parts of the centromere are included, leaving two centric chromosome fragments, one of which forms a small ring (Fig. 2a; Schuffenhauer et al., 1996). A second possible mechanism has been described for cases with sSRC(18) and sSRC(X): Here, sSRC were associated with complex chromosomal rearrangements (Stavropoulou et al., 1998; Stankiewicz et al., 2001). In all three of these cases a dicentric isochromosome could have been formed primarily (Stavropoulou et al., 1998), followed by an excision of one centromere, with the excised fragment subsequently forming a ring chromosome (see Fig. 2b). A third form of ring formation has been proposed in connection with an inverted duplication as due to a U-shape reunion between broken sister chromatids (see Fig. 2d; Michalski et al., 1993). For the overwhelming majority of sSRC we postulate a ring formation starting with a minute chromosome (Fig. 2e). In this case sSRC result, which do not have an inverted duplication. However, some ring chromosomes remain unexplained by any of these theories. For example, Fang et al. (1995) describe a complex sSRC, consisting of three different regions of chromosome 4. For such sSRC they postulate that they derive from an atypical large ring chromosome “which was involved in breakage and reunion cycles as a result of the formation of interlocked rings during cell division. As a consequence, complex deletions of DNA have occurred until the stable form was generated” (Fang et al., 1995). The formation of double rings is well known and is thought to be due to a sister chromatid exchange with a normal centromere division (Ramirez-Duenas and Gonzalez, 1992). Complex rearranged sSMC The majority of sSMC consist exclusively of material derived from one chromosome. Of those, only a very small subset does not consist of consecutive chromosomal material, but has complex intrachromosomal rearrangements (Fang et al., 1995; Schuffenhauer et al., 1996; Callen et al., 1999, cases A and C; Röthlisberger et al., 2000; Starke et al., 2001, 2003b, case 30; Daniel and Malafiej, 2003, case 5). There are some reports of sSMC derived from two (Uchida et al., 1964; Bröndum-Nielsen, 1991; Wolff and Schwartz, 1992; Pierluigi et al., 1997, 2 cases; Crolla et al., 1998, case 6; Viersbach et al., 1998, case 27; Arab et al., 1999; Hastings et al., 1999, case 8; Minelli et al., 2003) or three different chromosomes (Blennow et al., 1992). Here also sSMC resulting from meiotic malsegregation in carriers of a balanced reciprocal or Robertsonian translocation were included, as they were initial-

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ly detected as sSMC. sSMC present in der(22) syndrome consist of material from chromosome 11 and 22; the der(22) associated sSMC form the largest group among the complex sSMC (Shaikh et al., 1999).

Distribution of sSMC types in acrocentrics and non-acrocentrics sSMC can have different shapes (summarized in Fig. 1). An analysis of 1,528 cases included in this review (excluding 20 cases with multiple sSMC, 47 cases with neocentromeres and 132 cases with a karyotype 46,X,+mar) revealed the distribution illustrated in Fig. 5 for acrocentric and non-acrocentric chromosomes. Minute and ring chromosomes are present in 5.3 and 2.3 % of the acrocentrics but in 18.8 and 28.6 % of the non-acrocentrics, respectively. Acrocentric sSMC comprise preferentially inverted duplicated chromosomes (73.8 %). In the non-acrocentrics the inverted duplicated chromosomes are exclusively present as i(12p) and i(18p) chromosomes, accounting for 51.7 % of this group. Complex rearranged chromosomes comprising material derived from different chromosomes are, in general, a minority in all sSMC cases. However, as the sSMC present in the der(22) syndrome is a complex rearranged chromosome, this group comprises 18.6 % of the acrocentric cases (see Fig. 5).

Familial occurrence and mosaicism of sSMC Familial occurrence of sSMC Approximately 61 % of sSMC are de novo, with 39 % familial. These figures are based on a total of 174 cases from several studies (Nielsen and Rasmussen, 1975; Warburton, 1984; Hook and Cross, 1987; Sachs et al., 1987; Djalali, 1990; Blennow et al., 1994). In most of the familial cases there is no discernibly increased risk for fetal abnormalities if an sSMC is also present in a phenotypically normal parent (Bröndum-Nielsen and Mikkelsen, 1995). However, this does not hold true for all cases, especially when different grades of mosaicism are involved. For example in one reported family with a phenotypically normal father and son with neurological disorders and facial anomalies, the father had an sSMC derived from chromosome 7 present in 35 % of his cells, while the son had the sSMC in 100 % (Anderlid et al., 2001, cases H and I). Thus, sSMC presence in 35 % of the (blood) cells was without clinical consequences, while sSMC presence in all cells led to clinical abnormalities. Mosaicism in association with sSMC Mosaicism in association with sSMC is a well-known fact. Crolla (1998) summarized 144 cases, 78 of which (54 %) showed mosaic karyotypes. At least 60 % (i.e. 47) of those mosaic cases had psychomotor developmental delay and/or dysmorphic stigmata – apparently independent of the detected fraction of aberrant cells in the peripheral blood. An even lower rate of abnormal clinical findings was observed when looking at the non-mosaic cases; i.e. in 27 of 66 cases (40 %) clinical abnor-

Fig. 4. Chromosomal origin of 1,396 sSMC cases reviewed from the literature. Separated from the small supernumerary marker chromosomes not correlated with clinical syndromes (= sSMC) are cases with inverted duplication chromosomes 15 [inv dup (15)] and such cases with Pallister-Killian syndrome (PKS), isochromosome 18 [i(18p)] syndrome, derivative 22 [der(22)] syndrome and cat eye syndrome (CES). Additionally included are cases with neocentric sSMC and multiple sSMC of different chromosomal origin. The percentage in which each group appears within the collective is given in the right part of the figure. Fig. 5. sSMC derived from acrocentric or non-acrocentric chromosomes show different distributions of conformations: inverted duplication (yellow), ring (purple), complex rearranged (red) and minute chromosomes (blue) were distinguished. Fig. 6. Chromosomal origin of 857 sSMC cases (without those cases with multiple sSMC, with neocentric sSMC, with PKS, with CES, with der(22)-syndrome and with i(18p)-syndrome).


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malities were described (Crolla, 1998). Unfortunately, there are no systematic studies available to address that problem, e.g. by studying different tissues of the corresponding mosaicism carriers. Singular studies with in summary confusing results can be found in e.g. Viersbach et al. (1997), case 1; Anderlid et al. (2001), case N; Batista et al. (1995); Michalski et al. (1993), case 2; Felbor et al. (2002), case 2 (for overview see http://mti-n. mti.uni-jena.de/Fhuwww/MOL_ZYTO/sSMC.htm). More confusing examples of familial sSMC can be found in the literature. Similar grades of mosaicism in two generations but variations in the clinical outcome have been reported (TanSindhunata et al., 2000), as well as great variations in mosaicism with no phenotypic consequences (Anderlid et al., 2001, cases E and F plus B and C). The question of whether an sSMC is familial or derived de novo is easy to answer for most clinical cases. The problem of mosaicism and its consequences for the phenotype are, however, still not solved. Applying sophisticated molecular cytogenetic methods often leads to detection of more complex mosaics than initially detected by banding cytogenetics alone (e.g. cases 13, 33 and 35 in Starke et al., 2003b; Bartels et al., 2003). The latter, however, helps to interpret the severity of the clinical finding (e.g. Starke et al., 2003b, case 13). Additionally, one has to expect that sSMC may tend to rearrange and/or be reduced in size during karyotype evolution. This can lead to (1) sSRC with double ring formation (e.g. Starke et al., 2003b, case 13), (2) a minute chromosome of the same chromosomal region in a sub-population of the cells (e.g. Urioste et al., 1994, case III-2), or (3) the formation of different variants and a highly complex mosaic arising from minute or ring chromosomes being degraded in a subset of the studied cells (e.g. Starke et al., 2003b, case 33), (4) the disappearance of sSMC at least in the most frequently studied tissue, the peripheral blood (Fitzgerald and Mercer, 1980).

Frequency of sSMC Overall frequency in different populations Pooling data from the literature, sSMC are reported in 0.043 % (67 of 155,111) of newborn infants (Nielsen and Rasmussen, 1975; Hook and Hamerton, 1977; Buckon et al., 1980, 1985; Benn and Hsu, 1984; Nielsen and Wohlert, 1991; Maeda et al., 1991), in 0.076 % (244 of 319,303) of prenatal cases (Ferguson-Smith and Yates, 1984; Warburton, 1984; Hook and Cross, 1987; Sachs et al., 1987; Dahoun-Hadorn et al., 1990; Carrasco Juan et al., 1990; Djalali, 1990; Stengel-Rutkowski and Nummermann, 1991; Blennow et al., 1994; Bröndum-Nielsen and Mikkelsen, 1995; Li et al., 2000; Kaluzewski et al., 2001; Woo et al., 2003), in 0.426 % (82 of 19,243) of mentally retarded patients (Borgaonkar et al., 1971; Mulcahy and Jenkyn, 1972; Price et al., 1976; Buckton et al., 1985; Kirkilionis et al., 1987; Hou et al., 1998; Kaluzewski et al., 2001; Woo et al., 2003) and 0.165 % (19 of 11,548) of subfertile individuals (Johnson et al., 1974; Chandley et al., 1975; Bourrouillou et al., 1985; Buckton et al., 1985; Hens et al., 1988; Matsuda et al., 1989; Baschat et al., 1996; Testart et al., 1996; Pandiyan and Jequier, 1996; Tuerlings et al., 1998; Mau et al., 1997; Yoshida et al., 1997).

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Thus, sSMC are 10 and 4 times more frequent in mentally retarded and subfertile individuals respectively, compared to the overall population. Only two of the 18 reported cases with sSMC in subfertile people were female (Buckton et al., 1985). Nonetheless, the frequency of sSMC seems to be the same in males and females: 16 of 9,306 male (0.171 %) and 2 of 1,242 female (0.161 %) sSMC carriers, respectively. Moreover, it can be carefully deduced, that F0.033 % of unborn children are aborted after week 15 to 20 of pregnancy in association with the presence of an sSMC. However, this is biased by the fact that of 123 cases with sSMC detected prenatally, 37 were electively terminated and only 4 of the remaining 86 pregnancies ended with a stillbirth or spontaneous abortion; 9 additional cases of the 86 cases (10.5 %) were born with abnormalities (Warburton, 1991). sSMC in correlation to Down syndrome offspring or maternal age Other correlations of sSMC and clinical abnormalities have been studied. There is no increased risk for trisomy 21 in the offspring of sSMC carriers (Steinbach and Djalali, 1983); however, this result is still under discussion. A positive correlation between sSMC in the offspring and advanced maternal age has been reported (Chandley et al., 1975; Hook and Cross, 1987). This may be due to ascertainment bias, as the majority of women in these reports were studied due to enhanced maternal age and there were no younger control groups available. The problem of sSMC in connection with trisomic rescue and uniparental disomy is discussed later (see below). Frequencies of different sSMC groups For this paper we reviewed all available sSMC literature, i.e. 1750 reports. As it is impossible to include all references in this paper, the citations are available online on http://mtin.mti.uni-jena.de/Fhuwww/MOL_ZYTO/sSMC.htm or can be ordered from the author directly. About 2,000 cases with sSMC were characterized throughout these studies by cytogenetics and/or molecular cytogenetics. Only those 1,396 sSMC cases in which chromosomal origins were characterized reliably were included. These can be divided into (1) multiple sSMC, (2) sSMC with neo-centromeres, (3) sSMC correlated with known clinical syndromes and (4) sSMC not correlated with known clinical syndromes (see Fig. 4). Cases with Turner syndrome (karyotype 46,X,+mar) and Down syndrome (48,XY,+21,+mar or 48,XX,+21,+mar) were not included here. They are discussed separately below. Multiple sSMC The smallest group among the 1,396 cases (n = 20 cases, 1.4 %) comprises those with multiple sSMC derived from different chromosomes. Within this group there were 14 cases with two, two with four and one each with three, six and seven sSMC per case (for details see Table 1 and Fig. 4). A group consisting of 17 cases with 48 chromosomes and two identical small markers (derived from duplication of single sSMC) comprised the following: seven cases with derivatives of chromosome 15 (Martin-Lucas et al., 1986, cases 1 and 2; Manenti, 1992; Robinson et al., 1993a, case C; Nietzel et al.,

Table 1. Cases with two to seven sSMC of different origin Case No.

sSMC 1

sSMC 2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

r(3) min(3) r(6) r(X) mar(6) min(9) i(10) r(X) r(18) min(6) r(1) r(13 or 21) r(13 or 21) r(3) r(4) r(X) r(?5) min(1) r(1) min(X)

not characterized min(13) r(9) r(6) not characterized min(20) min(18) r(17) r(13) min(11) r(16) r(12) r(18) not characterized r(17) r(4) r(7) min(5) r(2) r(1)

sSMC 3

r(20) r(8) r(15) min(6) r(5) r(3)

2001, case 4; Qumsiyeh et al., 2003; Starke et al., 2003b, case 22), two cases with derivatives of chromosome 20 (Callen et al., 1991, case 10; Viersbach et al., 1997), and one case each with 2 identical sSMC of the X chromosome (Le Caignec et al., 2003), chromosome 3 (Rothemund et al., 1998), chromosome 6 (Stankiewicz et al., 2000), chromosome 9 (Mowrey et al., 2001), chromosome 12 (Van den Veyver et al., 1993), chromosome 13 (Warburton et al., 2000, case 13h), chromosome 17 (Engelen et al., 1996, case C) and chromosome 22 (Scott et al., 2003). These 17 cases are included within the groups “sSMC” and “inv dup(15)” of Fig. 4. sSMC with neocentromeres Forty-seven cases with sSMC (3.4 % of the 1,396 cases) including a neo-centromere are reported throughout the literature (for reviews and reports see Ramirez-Duenas and Gonzalez, 1992; Lamb et al., 1998; Siriwardena et al., 1999; Warburton et al., 2000; Dufke et al., 2001; Fritz et al., 2001; Amor and Choo, 2002; Hu et al., 2002; Li et al., 2002; Spiegel et al., 2003; Knegt et al., 2003). Nearly one quarter of the cases (11 of 47) is derived from chromosome 15, and 45 % originate from chromosomes 13, 3, 8 and 1 (see Fig. 3). If analphoid sSMC were screened for these five chromosomes, the origin should be clarified in 75 % of the cases. sSMC correlated with known clinical syndromes 33.8 % of the sSMC cases are correlated with known clinical syndromes (see Fig. 4). The Pallister-Killian (PKS; OMIM #601803) and isochromosome 18p [i(18p)] syndromes (Eggermann et al., 1999) are associated with isochromosomes 12p and 18p, respectively, in addition to well-defined clinical signs. In PKS the sSMC can be detected preferentially in fibroblasts and not in peripheral blood (OMIM #601803). A PKS associated i(12p) is present in almost 11 % and an i(18p) in 6 % of sSMC cases.

sSMC 4

r(10) r(22) min(7) r(6) r(11)

sSMC 5

r(12) min(14)

sSMC 6

sSMC 7

Reference

r(14 or 22) min(20)

Callen et al., 1991, case 2 Levy et al., 2002 Aalfs et al., 1996 Callen et al., 1991, case 3 Haddad et al., 1998, case 7 Starke et al., 2003b, case 34 Starke et al., 2003b, case 35 Wiktor et al., 1993 Nandi et al., 2001 Maurer et al., 2001 Shanske et al., 1999 Plattner et al., 1993a, b, case 20 Plattner et al., 1993a, b, case 21 Viersbach et al., 1998, case 28 Mackie-Oglivie et al., 1997, case 1 Mackie-Oglivie et al., 1997, case 2 Reddy et al., 2003, case 1 Reddy et al., 2003, case 2 Vermeesch et al., 1999 min(21) Ulmer et al., 1997

A derivative chromosome 22 [der(22)t(11;22)(q23;q11.2)] represents another F10 % of sSMC. It is “the only known recurrent, non-Robertsonian, constitutional translocation in humans. Carriers of the balanced constitutional t(11;22) are phenotypically normal but are at risk of having progeny with the supernumerary-der(22)t(11;22) syndrome, as a result of malsegregation of the der(22). Individuals with the +der(22) syndrome have a distinct phenotype, which consists of severe mental retardation (and physical) abnormalities” (Shaikh et al., 1999). The fourth known syndrome associated with sSMC is the cat eye syndrome (CES; OMIM #115470). In this case the sSMC is an inv dup(22) chromosome, which is present in F7 % of the cases with sSMC. inv dup(15) cases and sSMC not correlated with known clinical syndromes By far the largest group of sSMC (857 of 1,396 cases, 61.4 %) is not correlated with a specific syndrome. This group is divided into two almost equal sized subgroups: (i) those forming an inverted duplicated chromosome 15 (inv dup(15)) and (ii) those derived from all other chromosomes (see Fig. 4). The distribution of these remaining sSMC (Fig. 4) according to their chromosomal origin is shown in Fig. 6. Slightly more than half (F55 %) are comprised of chromosome 15 material. In summary, 71 % of those 857 sSMC cases discussed in this section derive from an acrocentric chromosome. Of the nonacrocentric cases, derivatives of chromosome 8 and 1 are the most frequent, with sSMC originating from chromosomes 21, 5, 6, 11, Y and 10 least frequently observed. There is no correlation of chromosome size and involvement in sSMC formation (see Fig. 6). 610 (F70 %) of those 857 cases of this sSMC group discussed here showed clinical symptoms, while 247 (F30 %) were healthy carriers of an sSMC. Approximately 50 % of the healthy sSMC carriers (some of those diagnosed during ICSI course) carried an sSMC derived


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from chromosome 15. Thus, chromosome 15 is over-represented in both groups: patients with clinical symptoms and healthy sSMC carriers. The patients with a der(15) sSMC are a clinically and cytogenetically heterogeneous group (Webb et al., 1998): about 50 cases with an inv dup(15)(q13) plus autism (e.g. Rineer et al., 1998), 27 cases with sSMC(15) plus PraderWilli syndrome (e.g. Narahara et al., 1992), 5 cases with sSMC(15) plus Angelman syndrome (e.g. Thompson and Bolton, 2003) and about 200 cases with different clinical symptoms correlated with the size of the sSMC (e.g. Roberts et al., 2003) are described. Finally, it has to be taken in account, that sSMC carriers with clinical symptoms are more likely to be reported than those without. Thus, a bias in direction of clinically abnormal cases cannot be excluded. sSMC in Down syndrome cases sSMC can also be detected in cases with free trisomy 21 and Down syndrome (OMIM #190685). Interestingly, at least 25 cases with trisomy 21 and an sSMC are reported in the literature. In only three of these the origin of the sSMC was identified. Two were derived from chromosome 15, and one from chromosome 4 (Heppell-Parton and Waters, 1991; Starke et al., 2003a, cases 10 and 23). The other 22 reports were published in the pre-FISH era and thus are not informative for this review. However, the Down syndrome phenotype did not seem to be altered by the presence of an additional sSMC. sSMC in Turner syndrome cases In Turner syndrome (OMIM #163950) a small subset of patients presents with a karyotype 45,X,+mar. 132 case reports are available in which the sSMC of Turner syndrome were characterized as derivatives of the X (e.g. Lin et al., 1990; Schwartz et al., 1997) or Y chromosome (e.g. Patsalis et al., 1998; Schwartz et al., 1997). According to Patsalis et al. (1998), there is some evidence that derivatives of the Y chromosomes are preferentially involved in Turner syndrome patients with sSMC; however, we could not confirm this, as we found 73 versus 59 case reports on X chromosome versus Y chromosome origin of the sSMC, respectively. Thus, a 1:1 distribution is most likely. As in Down syndrome, in general no phenotypic correlations are reported in connection with an additional sSMC in Turner syndrome. The exceptions are (1) when the sSMC comes from the Y chromosome the patient’s risk in developing either gonadoblastoma or another form of gonadal tumor is enhanced and (2) when the sSMC is derived from the X chromosome and the XIST locus is not present. In the latter cases, more clinical complications appear (Migeon et al., 1993).

sSMC and uniparental disomy (UPD) Uniparental disomy (UPD), the exceptional inheritance of two homologous chromosomes from only one parent, has been shown to occur in cases with sSMC (for review see Kotzot, 2002; Shaffer et al., 2001; Starke et al., 2003b, Fig. 6). Predicting the phenotypic effects of UPD is complex as, according to

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Ledbetter and Engel (1995), three independent factors are involved: (i) effects of trisomy on the placenta or the fetus; (ii) autosomal recessive disease due to reduction to homozygosity, and (iii) imprinted gene effects for some chromosomes. Moreover, the situation can be complicated by the finding of heterodisomy combined with isodisomy (e.g. Salafsky et al., 2001). UPD is without clinical consequences for some chromosomes (e.g. von Eggeling et al., 2002), but for a few chromosomes (6, 7, 11, 14, 15 and 20) it can result in abnormality in the affected individual (Chudoba et al., 1999; Shaffer et al., 2001; Kotzot, 2002). There are only a few systematic studies for UPD in connection with sSMC (James et al., 1995; Anderlid et al., 2001; Starke et al., 2003b). Nonetheless, there are 160 cases in total, which were studied for UPD of the sSMC’s sister-chromosomes and a UPD was detected in sixteen (10 %). UPD 15 in association with Prader-Willi or Angelman syndrome has been described five times (Robinson et al., 1993b; Cheng et al., 1994; Bettio et al., 1996; Mignon et al., 1996; Roberts et al., 2002); UPD 1 (Röthlisberger et al., 2001; Finelli et al., 2001) and UPD 7 (Miyoshi et al., 1999; own unpublished data) was detected twice, each. Partial UPD 4 (Starke et al., 2003b, case 10), UPD 6 (James et al., 1995), UPD 9 (Anderlid et al., 2001, case L), UPD 10 (Schlegel et al., 2002), UPD 12 (von Eggeling et al., 2002), UPD 20 (Chudoba et al., 1999) and UPD 22 (Bartels et al., 2003) were all found in single cases. Cases with der(22) syndrome are excluded here, as they all have, due to their mode of formation, partial UPD(22) and UPD(11) (e.g. Starke et al., 2003b, case 29).

Classification of sSMC To facilitate the description of sSMC based on novel molecular cytogenetic characterization, we previously proposed a new sSMC classification (Tables 4 and 5 in Starke et al., 2003b), based on five main classes that are differentiated by the presence or absence of a nucleolar organizer region (NOR)/centromeric region and a rearrangement of the sSMC. sSMC derived from acrocentric chromosomes (including all minutes, dicentrics, ring chromosomes, and other rearrangements) are summarized in class 1; in class 2, sSMC derived from all other chromosomes apart from the acrocentrics are included (as long as they do not comprise any detectable rearrangements); class 3 and 4 comprise complex rearranged chromosomes, class 3 those which are rearranged with own chromosomal material, class 4 those which are rearranged with others; class 5, finally, includes neocentric sSMC. Furthermore, four subclasses are suggested that allow for the presence or absence of pericentromeric euchromatin and/or UPD: class a = neither centromerenear material, nor UPD; class b = no centromere-near material, UPD present; class c = centromere-near material present, no UPD; class d = centromere-near material plus UPD present.

Table 2. Suggestion for the management of prenatally diagnosed sSMC – as well under aspect of ongoing research. Adapted from Hastings et al. (1999)

Suggestion for the management of prenatally diagnosed sSMC 1. 2. 3. 4.

5. 6. 7. 8.

9.

Presence of an sSMC noted: Take parental blood samples for karyotyping (heparinized blood) and UPD test (EDTA-blood). Identify composition and origin of sSMC using appropriate molecular-cytogenetic techniques. If diagnosed in cultured amniocytes in more than one culture/multiple coverslips or in fetal lymphocytes, no further invasive testing is indicated. If diagnosed in chorionic villus, further confirmation by fetal blood sampling or amniocentesis is strongly recommended. Perform microsatellite analysis to exclude an uniparental disomy (UPD) of the sSMC’s sister-chromosomes. Ultrasound scan examination looking for fetal anomalies. Counsel parents regarding likely phenotype. If the parents elect to terminate the pregnancy, collect fetal tissue for confirmation of result and encourage post-mortem. In mosaic cases it may be appropriate to sample several tissues. If the parents do not elect to terminate the pregnancy, obtain follow-up clinical information regarding infant at birth and during childhood. Request a blood sample for further cytogenetic studies if origin not ascertained prenatally. Whenever possible, tissue or blood with an sSMC should be stored for future studies; this can be done in our lab (Institute of Human Genetics, Jena; please contact Dr. Thomas Liehr: [email protected]).

sSMC characterization by cytogenetics, molecular cytogenetics and molecular genetics Detection of an sSMC is nearly always unexpected by the clinician and more or less an accidental result in cytogenetics. As pointed out previously (Starke et al., 2003b), the origin of sSMC is almost impossible to establish by routine cytogenetics alone, whereas FISH methods are highly suited for this. sSMC have been successfully characterized by whole-chromosomepainting (WCP) probes, centromere-specific probes, combined chromosome microdissection plus reverse painting and FISH approaches (for a review, see Nietzel et al., 2001) and comparative genomic hybridization (e.g. Levy et al., 2002). WCP-FISH approaches are well suited for the determination of the chromosomal origin of marker or derivative chromosomes providing that they are larger than 17p. If they are smaller than this, WCP-FISH is, in general, non-informative (Haddad et al., 1998, case 7, mar 1; Starke et al., 1999). As recently reported, for sSMC with a euchromatic content of approximately half of the short arm of chromosome 17p or more, characterization by the multicolor banding (MCB) technique is possible (Weise et al., 2002; Starke et al., 2003b). For a fast and easy characterization of sSMC we recently proposed the centromere-specific multicolor FISH (cenM-FISH) method (Nietzel et al., 2001). Despite this, analyses of sSMC to detect the presence of euchromatin to date have been ambiguous and have required further clarification. In the recent paper of Starke et al. (2003b), we have addressed this problem by utilizing a probe-set comprising 43 bacterial or yeast artificial chromosome (BAC or YAC, respectively) clones located in the proximal regions of each human chromosome, called subcentromeric multicolor-FISH (subcenM-FISH). We and others (Chudoba et al., 1999; von Eggeling et al., 2002; reviewed in Kotzot, 2002), previously recommended that, after identification of the origin of the SMC, its normal sister-chromosomes should be tested for their parental origin to exclude a possible UPD. UPD can be tested by molecular genetic approaches, such as microsatellite analysis (Salafsky et al., 2001) or methylation-specific polymerase chain reaction (PCR) (Nietzel et al., 2003) and at the present state of

research, according to our opinion, should be done for every sSMC case in which parental cell material is available. A possible strategy for dealing with sSMC cases is summarized in Table 2.

Towards a clinical correlation of sSMC Great advances were achieved especially in the recent years both in sSMC characterization and insight into their clinical impact. Between 1961 and the end of the 1970’s no specific clinical syndrome was characterized among the sSMC cases. The der(22) and the cat eye syndromes (CES) were the first to be identified (Fraccaro et al., 1980; Schinzel et al., 1981), followed by the Pallister-Killian Syndrome (PKS) (Peltomaki et al., 1987) and the i(18p) syndrome. The latter was unambiguously confirmed to be due to partial tetrasomy 18p by application of radioactive in situ hybridization in 1990 (Callen et al., 1990). The introduction of UPD studies in sSMC cases was the next milestone (James et al., 1995). When Crolla (1998) published the first major review on sSMC, it was additionally clear that the inverted duplicated chromosomes derived from chromosome 15 constituted a specific subgroup and, as suggested in 1993 (Robinson et al., 1993a), the clinical severity of cases with inv dup(15) is associated with the presence and dosage of the Prader-Willi/Angelman syndrome critical region (OMIM #176270, #105830) rather than with differences in the extent of the duplicated segment (Nietzel et al., 2003). During the next 10 years (starting from 1993) many sSMC cases were studied by various approaches. But up to the description of the subcenM approach (Starke et al., 2003b), no considerable progress concerning the problem of centromere-associated proximal trisomy and phenotype-associated risk evaluation was done. Thus, up to the present time approximately 30 % of sSMC still lack a clinical correlation (see also Fig. 4). Recently we reported 35 cases of sSMC which were comprehensively studied for their euchromatic content and, where possible, as well for presence of UPD of the sister chromosomes (Starke et al., 2003b). Based on this study and from data from


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the literature we were able to provide a first step toward the identification of pericentromeric disease-related genes. All sSMC without euchromatic content and no UPD turned out to be harmless. Psychomotor or mental retardation and/or dysmorphic signs could be observed in connection with an sSMC and the presence of additional euchromatic content derived from chromosomes 1p, 1q, 2p, 7q, 9p, or 12q. Imbalances in the juxtacentromeric region of 2q, 3p, 4q, 5q, 7p, 8p, 17p, 18p, 19p/19q, and 22q (excluding the cat eye syndrome critical region in 22q11.2 → 3) were without clinical consequences. The study of Starke et al. (2003b) has revealed clinical correlations in connection with sSMC formation and partial proximal trisomies for 18 of the 43 centromere-near regions of the human

genome. However, these data are based in parts on single cases and need to be complemented by further studies (see as well Table 3 in Starke et al., 2003b). This review combined with the highly informative recently described molecular cytogenetic approaches (Nietzel et al., 2001; Trifonov et al., 2003; Starke et al., 2001, 2003b) should it make more feasible for the clinician to do genetic counseling of parents expecting children with de novo sSMC.

Acknowledgements The authors thank Dr. Lyndal Kearney (London, UK) for very helpful suggestions and discussions.

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