small supernumerary marker chromosomes (ssmc) in...

Original Article

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

Small supernumerary marker chromosomes(sSMC) in humansT. Liehr, U. Claussen, and H. StarkeInstitute of Human Genetics and Anthropology, Jena (Germany)

Supported by the Dr. Robert Pfleger-Stiftung.

Received 29 March 2004; manuscript accepted 18 May 2004.

Request reprints from Dr. Thomas Liehr, Institut für HumangenetikPostfach, DE–07740 Jena (Germany); telephone: +49 3641 935533fax: +49 3641 935502; e-mail: [email protected]

ABC Fax + 41 61 306 12 34E-mail [email protected]

© 2004 S. Karger AG, Basel0301–0171/04/1072–0055$21.00/0

Accessible online at:www.karger.com/cgr

Abstract. Small supernumerary marker chromosomes(sSMC), defined as additional centric chromosome fragmentstoo small to be identified or characterized unambiguously bybanding cytogenetics alone, are present in 0.043% of newbornchildren. Several attempts have been made to correlate certainsSMC with a specific clinical picture, resulting in the descrip-tion of several syndromes such as the i(18p)-, der(22)-, i(12p)-(Pallister Killian syndrome) and inv dup(22)- (cat-eye) syn-dromes. However, most of the remaining sSMC including min-ute-, ring-, inverted-duplication- as well as complex-rearrangedchromosomes, have not yet been correlated with clinical syn-dromes, mostly due to problems in their comprehensive char-

acterization. Here we present an overview of sSMC, includingthe first attempt to address problems of nomenclature and theirmodes of formation, problems connected with mosaicism plusfamilial occurrence. The review also discusses the frequency ofsSMC in prenatal, postnatal, and clinical cases, their chromo-somal origin and their association with uniparental disomy. Ashort review of the up-to-date approaches available for sSMCcharacterization is included. Clinically relevant correlationsconcerning the presence of a specific sSMC and its phenotypicconsequences should become available soon.

Copyright © 2004 S. Karger AG, Basel

Overview on sSMC

The report most often cited as the first description of a smallsupernumerary marker chromosome (sSMC; the abbreviationsSMC is used throughout this review irrespective if we talk ofone small supernumerary marker chromosome or of two ormore marker chromosomes) is Froland et al. (1963). However,this was in fact the third sSMC case, preceded by Ellis andcoworkers (1962) who reported “an aberrant small acrocentricchromosome”, and Ilberry and coworkers (1961).

A clear definition of sSMC is conspicuously lackingthroughout the corresponding literature. Crolla proposed a“minimal definition” for sSMC as “small structurally abnormal

chromosomes that occur in addition to the normal 46 chromo-somes” (Crolla et al., 1997). Part of the problem is that the phe-notypes associated with sSMC are hugely variable, from nor-mal to severely abnormal (Paoloni-Giacobino et al., 1998). Pre-natally ascertained cases with small markers which have arisende novo are particularly difficult to associate with a clinical out-come. The correlation of specific sSMC with distinct clinicalpictures has been possible for some syndromes, for example thei(18p) syndrome, i(12p)- (Pallister-Killian) syndrome, der(22)-and cat-eye syndromes (Crolla, 1998). In general, the risk for anabnormal phenotype in prenatally ascertained de novo caseswith sSMC is given as F13% (Warburton, 1991); i.e. 7% forsSMC from chromosomes 13, 14, 21 or 22 and 28% for non-acrocentric chromosomes (Crolla, 1998).

In summary, 1,528 cases with sSMC characterized by mo-lecular cytogenetic methods for their chromosomal origin wereincluded in this review; 1,396 of those cases had at least 47chromosomes, the remaining 132 had 46 chromosomes and aTurner syndrome-like appearance. Additionally, for the re-viewed data on sSMC frequencies in different populations, 427sSMC cases of unknown chromosomal origin were included.An sSMC not characterizable by fluorescence in situ hybridiza-

56 Cytogenet Genome Res 107:55–67 (2004)

tion (FISH) described by Mackie Ogilvie et al. (2001) andsSMC detected in tumor cytogenetics were not included in thisreview.

Nomenclature and definition of sSMC

Nomenclature of sSMCsSMC were given various names throughout the last de-

cades. The three best known are: “SMC”, which does not distin-guish between larger and smaller supernumerary marker chro-mosomes (e.g. Crolla, 1998), extra structurally abnormal chro-mosome (= ESAC; e.g. Hook and Cross, 1987) and supernu-merary ring chromosome (= SRC; e.g. Blennow et al., 1994). Itis stated that SRC constitute about 10% of SMC (Blennow etal., 1994). In addition, the following names can be found: acces-sory chromosome (= AC; Soudek and Sroka, 1977; or ACH;Soudek et al., 1973), small accessory chromosome (= SAC; Ver-meesch et al., 1999), marker chromosome (Nielsen and Ras-mussen, 1975), extra or additional marker chromosome (Buck-ton et al., 1985; Martin et al., 1986), supernumerary or extramicrochromosome (Howard-Peebles, 1979; Chudley et al.,1983), additional or metacentric chromosome fragment (DenDulk et al., 1966), (centric) fragment (Hoehn et al., 1970), orsmall bisatellited additional chromosome (= SBAC; Mattei etal., 1984).

The ISCN defines “marker” chromosome as “an abnormalchromosome 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 wasidentified” (Callen et al., 1999).

Definition of sSMCsSMC are a morphologically heterogeneous group of struc-

turally abnormal chromosomes: different types of invertedduplicated chromosomes, minute chromosomes and ring chro-mosomes can be detected (see Fig. 1). Thus, the description ofsSMC 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 forthe first time a cytogenetic one as follows: sSMC are structurallyabnormal chromosomes that cannot be identified or character-ized unambiguously by conventional banding cytogeneticsalone, and are (in general) equal in size or smaller than a chro-mosome 20 of the same metaphase spread (see Fig. 1). sSMCcan be present additionally (1) in a karyotype of 46 normalchromosomes, (2) in a numerically abnormal karyotype (likeTurner or Down syndrome) or (3) in a structurally abnormalbut balanced karyotype (e.g. Robertsonian translocation; Wolffand Schwartz, 1992) or ring chromosome formation (e.g. LasanTrcic et al., 2003).

In contrast, a SMC larger than chromosome 20 usually canbe identified based on chromosome banding. Thus, cases withi(9p) are not included in the group of sSMC in this review, aspreviously done (see e.g. Viersbach et al., 1998). The definitionof small SMC versus large(r) SMC is a cytogenetic, not a “func-tional” one, i.e. sSMC and larger SMC can have the samemodes of karyotypic evolution (see below).

sSMC formation

Different mechanisms of sSMC formation including tri-somic rescue, monosomic rescue, post fertilization errors andgamete complementation have been proposed in the literature(Bartels et al., 2003). Mosaicism resulting in one cell line withsSMC and one with a trisomy provided evidence for functionaltrisomic rescue as a really existing mechanism (Bartels et al.,2003).

Recently, a new mechanism was proposed, in which sSMCoriginated from transfection of chromosomes into the zygotederived from one or more superfluous haploid pronuclei thatwould normally be degraded by deoxyribonucleases or othermeans (Daniel and Malafiej, 2003). This provides a possibleexplanation for the formation of multiple sSMC of differentorigin.

Inverted duplication chromosomesSeveral modes of formation for inverted duplication (acro-

centric) chromosomes (see Fig. 1) have been proposed (Schrecket al., 1977; Ing et al., 1987; Narahara et al., 1992). The mostplausible of these is a U-type exchange resulting from crossovermistakes of chromatids of two homologous chromosomes dur-ing meiosis (Schreck et al., 1977; see Fig. 2c). A U-typeexchange is also proposed for the formation of isochromosomesof non-acrocentric chromosomes this time with a break withinthe centromeric DNA (Dewald, 1983). This is a more generalmechanism of isochromosome formation present not only ingerm cells, but also in tumor cells (Mukherjee et al., 1991).

Neocentric chromosomesIn recent years, an increasing number of supernumerary

human marker chromosomes have been reported with cen-tromeres that contain no detectable alpha-satellite DNA. Theseso-called analphoid markers “carry newly derived centromeres(or ‘neocentromeres’) that are apparently formed within inter-stitial chromosomal sites that have not previously been knownto express centromere function” (Choo, 1997).

The development of the majority of neocentric sSMC isbased on a U-type exchange (see Fig. 2c; Voullaire et al., 2001).Most of the neocentric sSMC included in this review (seeFig. 3) are small isochromosomes. The acentric fragmentcreated during an U-type exchange in these cases is includedinto a gamete, a neo-centromere is activated and the new chro-mosome (-fragment) is distributed throughout further cell cy-cles. This theory is supported by the fact that the frequency ofinv dup(15) chromosomes is similar to that observed in neo-centric chromosomes 15 among other acrocentric derived chro-mosomes of the corresponding groups. As shown in Fig. 3, 11 ofthe 18 cases derived from acrocentrics (i.e. F60%) are derivedfrom chromosome 15. About half of the cases summarized inFig. 4 are centric acrocentric sSMC, thus also F60% of thisgroup 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. Themechanism for ring chromosome formation shown in Fig. 2a

Cytogenet Genome Res 107:55–67 (2004) 57

Fig. 1. Small supernumerary marker chromosomes (sSMC) can have different forms; they can appear as inverted duplicationchromosomes (inv dup), minute chromosomes (min) or ring chromosomes (r). We define sSMC as small structurally abnormalchromosomes, in general equal in size or smaller than a chromosome 20 of the same metaphase spread, as larger SMC can usuallybe characterized by banding cytogenetics.

Fig. 2. The postulated different modes of sSMC formation are summarized here. Ring chromosome formation can be (a) dueto an interstitial deletion, (b) arise connected with a complex chromosomal rearrangement leading to an inverted duplication priorto the formation of a ring, (d) in connection with a U-shape reunion between broken sister chromatids leading to an invertedduplicated 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; fornon-acrocentric iso-chromosomes the same U-type exchange during meiosis is thought to be the most likely explanation for sSMCformation, as well. In the lower part of c, the evolution of a neocentric chromosome in connection with a U-type exchange isdepicted.

Fig. 3. 47 cases with neocentric sSMC are reported in the literature. Their distribution according to the chromosomal origin isshown here.

#20 inv dup } min }

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appeared in the aforementioned cases: a part of the chromo-some is excised by unknown mechanisms and for unknown rea-sons and a neocentric chromosome is built, while the originalcentromere stays at the shortened chromosome (Schuffenhaueret al., 1996).

Small supernumerary ring chromosomes (sSRC)Several possible explanations for formation of non-neocen-

tric small supernumerary ring chromosomes (sSRC) are avail-able.

Firstly, sSRC can be formed in association with a deletion ofa part of the chromosome; in contrast to neocentric sSMC,parts of the centromere are included, leaving two centric chro-mosome fragments, one of which forms a small ring (Fig. 2a;Schuffenhauer et al., 1996). A second possible mechanism hasbeen described for cases with sSRC(18) and sSRC(X): Here,sSRC were associated with complex chromosomal rearrange-ments (Stavropoulou et al., 1998; Stankiewicz et al., 2001). Inall three of these cases a dicentric isochromosome could havebeen formed primarily (Stavropoulou et al., 1998), followed byan excision of one centromere, with the excised fragment subse-quently forming a ring chromosome (see Fig. 2b).

A third form of ring formation has been proposed in connec-tion with an inverted duplication as due to a U-shape reunionbetween broken sister chromatids (see Fig. 2d; Michalski et al.,1993).

For the overwhelming majority of sSRC we postulate a ringformation starting with a minute chromosome (Fig. 2e). In thiscase sSRC result, which do not have an inverted duplication.

However, some ring chromosomes remain unexplained byany of these theories. For example, Fang et al. (1995) describe acomplex sSRC, consisting of three different regions of chromo-some 4. For such sSRC they postulate that they derive from anatypical large ring chromosome “which was involved in break-age and reunion cycles as a result of the formation of inter-locked rings during cell division. As a consequence, complexdeletions of DNA have occurred until the stable form was gen-erated” (Fang et al., 1995).

The formation of double rings is well known and is thoughtto be due to a sister chromatid exchange with a normal cen-tromere division (Ramirez-Duenas and Gonzalez, 1992).

Complex rearranged sSMCThe majority of sSMC consist exclusively of material de-

rived from one chromosome. Of those, only a very small subsetdoes not consist of consecutive chromosomal material, but hascomplex 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 (Uchidaet 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 chromo-somes (Blennow et al., 1992). Here also sSMC resulting frommeiotic malsegregation in carriers of a balanced reciprocal orRobertsonian translocation were included, as they were initial-

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

Distribution of sSMC types in acrocentrics andnon-acrocentrics

sSMC can have different shapes (summarized in Fig. 1). Ananalysis of 1,528 cases included in this review (excluding 20cases with multiple sSMC, 47 cases with neocentromeres and132 cases with a karyotype 46,X,+mar) revealed the distribu-tion illustrated in Fig. 5 for acrocentric and non-acrocentricchromosomes. Minute and ring chromosomes are present in5.3 and 2.3% of the acrocentrics but in 18.8 and 28.6% of thenon-acrocentrics, respectively. Acrocentric sSMC comprisepreferentially inverted duplicated chromosomes (73.8%). Inthe non-acrocentrics the inverted duplicated chromosomes areexclusively present as i(12p) and i(18p) chromosomes, account-ing for 51.7% of this group. Complex rearranged chromosomescomprising material derived from different chromosomes are,in general, a minority in all sSMC cases. However, as the sSMCpresent in the der(22) syndrome is a complex rearranged chro-mosome, this group comprises 18.6% of the acrocentric cases(see Fig. 5).

Familial occurrence and mosaicism of sSMC

Familial occurrence of sSMCApproximately 61% of sSMC are de novo, with 39% famil-

ial. These figures are based on a total of 174 cases from severalstudies (Nielsen and Rasmussen, 1975; Warburton, 1984;Hook and Cross, 1987; Sachs et al., 1987; Djalali, 1990; Blen-now et al., 1994). In most of the familial cases there is no dis-cernibly increased risk for fetal abnormalities if an sSMC is alsopresent in a phenotypically normal parent (Bröndum-Nielsenand Mikkelsen, 1995). However, this does not hold true for allcases, especially when different grades of mosaicism are in-volved. For example in one reported family with a phenotypi-cally normal father and son with neurological disorders andfacial anomalies, the father had an sSMC derived from chro-mosome 7 present in 35% of his cells, while the son had thesSMC in 100% (Anderlid et al., 2001, cases H and I). Thus,sSMC presence in 35% of the (blood) cells was without clinicalconsequences, while sSMC presence in all cells led to clinicalabnormalities.

Mosaicism in association with sSMCMosaicism 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 mosa-ic cases had psychomotor developmental delay and/or dys-morphic stigmata – apparently independent of the detectedfraction of aberrant cells in the peripheral blood. An even lowerrate of abnormal clinical findings was observed when looking atthe 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 supernumerarymarker chromosomes not correlated with clinical syndromes (= sSMC) are cases with inverted duplication chromosomes 15 [invdup (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 differentchromosomal 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).


malities were described (Crolla, 1998). Unfortunately, there areno systematic studies available to address that problem, e.g. bystudying different tissues of the corresponding mosaicism car-riers. Singular studies with in summary confusing results can befound in e.g. Viersbach et al. (1997), case 1; Anderlid et al.(2001), case N; Batista et al. (1995); Michalski et al. (1993), case2; 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 inthe literature. Similar grades of mosaicism in two generationsbut variations in the clinical outcome have been reported (Tan-Sindhunata et al., 2000), as well as great variations in mosai-cism 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 denovo is easy to answer for most clinical cases. The problem ofmosaicism and its consequences for the phenotype are, how-ever, still not solved. Applying sophisticated molecular cyto-genetic methods often leads to detection of more complexmosaics 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 theclinical finding (e.g. Starke et al., 2003b, case 13).

Additionally, one has to expect that sSMC may tend to rear-range 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 thesame chromosomal region in a sub-population of the cells (e.g.Urioste et al., 1994, case III-2), or (3) the formation of differentvariants and a highly complex mosaic arising from minute orring chromosomes being degraded in a subset of the studiedcells (e.g. Starke et al., 2003b, case 33), (4) the disappearance ofsSMC at least in the most frequently studied tissue, the periph-eral blood (Fitzgerald and Mercer, 1980).

Frequency of sSMC

Overall frequency in different populationsPooling data from the literature, sSMC are reported in

0.043% (67 of 155,111) of newborn infants (Nielsen and Ras-mussen, 1975; Hook and Hamerton, 1977; Buckon et al., 1980,1985; Benn and Hsu, 1984; Nielsen and Wohlert, 1991; Maeda etal., 1991), in 0.076% (244 of 319,303) of prenatal cases (Fergu-son-Smith and Yates, 1984; Warburton, 1984; Hook and Cross,1987; Sachs et al., 1987; Dahoun-Hadorn et al., 1990; CarrascoJuan et al., 1990; Djalali, 1990; Stengel-Rutkowski and Num-mermann, 1991; Blennow et al., 1994; Bröndum-Nielsen andMikkelsen, 1995; Li et al., 2000; Kaluzewski et al., 2001; Woo etal., 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% (19of 11,548) of subfertile individuals (Johnson et al., 1974; Chand-ley 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).

Thus, sSMC are 10 and 4 times more frequent in mentallyretarded and subfertile individuals respectively, compared tothe overall population. Only two of the 18 reported cases withsSMC in subfertile people were female (Buckton et al., 1985).Nonetheless, the frequency of sSMC seems to be the same inmales and females: 16 of 9,306 male (0.171%) and 2 of 1,242female (0.161%) sSMC carriers, respectively.

Moreover, it can be carefully deduced, that F0.033% ofunborn children are aborted after week 15 to 20 of pregnancy inassociation with the presence of an sSMC. However, this isbiased by the fact that of 123 cases with sSMC detected prena-tally, 37 were electively terminated and only 4 of the remaining86 pregnancies ended with a stillbirth or spontaneous abortion;9 additional cases of the 86 cases (10.5%) were born withabnormalities (Warburton, 1991).

sSMC in correlation to Down syndrome offspring ormaternal ageOther correlations of sSMC and clinical abnormalities have

been studied. There is no increased risk for trisomy 21 in theoffspring of sSMC carriers (Steinbach and Djalali, 1983); how-ever, this result is still under discussion. A positive correlationbetween sSMC in the offspring and advanced maternal age hasbeen reported (Chandley et al., 1975; Hook and Cross, 1987).This may be due to ascertainment bias, as the majority of wom-en in these reports were studied due to enhanced maternal ageand there were no younger control groups available. The prob-lem of sSMC in connection with trisomic rescue and uniparen-tal disomy is discussed later (see below).

Frequencies of different sSMC groupsFor this paper we reviewed all available sSMC literature, i.e.

1750 reports. As it is impossible to include all references in thispaper, the citations are available online on http://mti-n.mti.uni-jena.de/Fhuwww/MOL_ZYTO/sSMC.htm or canbe ordered from the author directly. About 2,000 cases withsSMC were characterized throughout these studies by cytoge-netics and/or molecular cytogenetics. Only those 1,396 sSMCcases in which chromosomal origins were characterized reliablywere included. These can be divided into (1) multiple sSMC,(2) sSMC with neo-centromeres, (3) sSMC correlated withknown clinical syndromes and (4) sSMC not correlated withknown clinical syndromes (see Fig. 4).

Cases with Turner syndrome (karyotype 46,X,+mar) andDown syndrome (48,XY,+21,+mar or 48,XX,+21,+mar) werenot included here. They are discussed separately below.

Multiple sSMCThe smallest group among the 1,396 cases (n = 20 cases,

1.4%) comprises those with multiple sSMC derived from dif-ferent chromosomes. Within this group there were 14 caseswith two, two with four and one each with three, six and sevensSMC per case (for details see Table 1 and Fig. 4).

A group consisting of 17 cases with 48 chromosomes andtwo identical small markers (derived from duplication of singlesSMC) comprised the following: seven cases with derivatives ofchromosome 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 sSMC 3 sSMC 4 sSMC 5 sSMC 6 sSMC 7 Reference

1 r(3) not characterized Callen et al., 1991, case 2 2 min(3) min(13) Levy et al., 2002 3 r(6) r(9) Aalfs et al., 1996 4 r(X) r(6) Callen et al., 1991, case 3 5 mar(6) not characterized Haddad et al., 1998, case 7 6 min(9) min(20) Starke et al., 2003b, case 34 7 i(10) min(18) Starke et al., 2003b, case 35 8 r(X) r(17) Wiktor et al., 1993 9 r(18) r(13) Nandi et al., 2001

10 min(6) min(11) Maurer et al., 2001 11 r(1) r(16) Shanske et al., 1999 12 r(13 or 21) r(12) Plattner et al., 1993a, b, case 20 13 r(13 or 21) r(18) Plattner et al., 1993a, b, case 21 14 r(3) not characterized Viersbach et al., 1998, case 28 15 r(4) r(17) r(20) Mackie-Oglivie et al., 1997, case 1 16 r(X) r(4) r(8) r(10) Mackie-Oglivie et al., 1997, case 2 17 r(?5) r(7) r(15) r(22) Reddy et al., 2003, case 1 18 min(1) min(5) min(6) min(7) Reddy et al., 2003, case 2 19 r(1) r(2) r(5) r(6) r(12) r(14 or 22) Vermeesch et al., 1999 20 min(X) r(1) r(3) r(11) min(14) min(20) min(21) Ulmer et al., 1997

2001, case 4; Qumsiyeh et al., 2003; Starke et al., 2003b, case22), two cases with derivatives of chromosome 20 (Callen et al.,1991, case 10; Viersbach et al., 1997), and one case each with 2identical sSMC of the X chromosome (Le Caignec et al., 2003),chromosome 3 (Rothemund et al., 1998), chromosome 6 (Stan-kiewicz 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 etal., 1996, case C) and chromosome 22 (Scott et al., 2003). These17 cases are included within the groups “sSMC” and “invdup(15)” of Fig. 4.

sSMC with neocentromeresForty-seven cases with sSMC (3.4% of the 1,396 cases)

including a neo-centromere are reported throughout the litera-ture (for reviews and reports see Ramirez-Duenas and Gonza-lez, 1992; Lamb et al., 1998; Siriwardena et al., 1999; Warbur-ton et al., 2000; Dufke et al., 2001; Fritz et al., 2001; Amor andChoo, 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) isderived from chromosome 15, and 45% originate from chro-mosomes 13, 3, 8 and 1 (see Fig. 3). If analphoid sSMC werescreened for these five chromosomes, the origin should be clari-fied in 75% of the cases.

sSMC correlated with known clinical syndromes33.8% of the sSMC cases are correlated with known clinical

syndromes (see Fig. 4).The Pallister-Killian (PKS; OMIM #601803) and isochro-

mosome 18p [i(18p)] syndromes (Eggermann et al., 1999) areassociated with isochromosomes 12p and 18p, respectively, inaddition to well-defined clinical signs. In PKS the sSMC can bedetected preferentially in fibroblasts and not in peripheralblood (OMIM #601803). A PKS associated i(12p) is present inalmost 11% and an i(18p) in 6% of sSMC cases.

A derivative chromosome 22 [der(22)t(11;22)(q23;q11.2)]represents another F10% of sSMC. It is “the only knownrecurrent, non-Robertsonian, constitutional translocation inhumans. Carriers of the balanced constitutional t(11;22) arephenotypically normal but are at risk of having progeny withthe supernumerary-der(22)t(11;22) syndrome, as a result ofmalsegregation of the der(22). Individuals with the +der(22)syndrome have a distinct phenotype, which consists of severemental retardation (and physical) abnormalities” (Shaikh et al.,1999).

The fourth known syndrome associated with sSMC is thecat eye syndrome (CES; OMIM #115470). In this case thesSMC 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 knownclinical syndromesBy far the largest group of sSMC (857 of 1,396 cases, 61.4%)

is not correlated with a specific syndrome. This group isdivided into two almost equal sized subgroups: (i) those form-ing an inverted duplicated chromosome 15 (inv dup(15)) and(ii) those derived from all other chromosomes (see Fig. 4). Thedistribution of these remaining sSMC (Fig. 4) according totheir chromosomal origin is shown in Fig. 6. Slightly more thanhalf (F55%) are comprised of chromosome 15 material.

In summary, 71% of those 857 sSMC cases discussed in thissection derive from an acrocentric chromosome. Of the non-acrocentric cases, derivatives of chromosome 8 and 1 are themost frequent, with sSMC originating from chromosomes 21,5, 6, 11, Y and 10 least frequently observed. There is no correla-tion of chromosome size and involvement in sSMC formation(see Fig. 6). 610 (F70%) of those 857 cases of this sSMC groupdiscussed here showed clinical symptoms, while 247 (F30%)were healthy carriers of an sSMC.

Approximately 50% of the healthy sSMC carriers (some ofthose diagnosed during ICSI course) carried an sSMC derived


from chromosome 15. Thus, chromosome 15 is over-repre-sented in both groups: patients with clinical symptoms andhealthy sSMC carriers. The patients with a der(15) sSMC are aclinically 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 Prader-Willi syndrome (e.g. Narahara et al., 1992), 5 cases withsSMC(15) plus Angelman syndrome (e.g. Thompson and Bol-ton, 2003) and about 200 cases with different clinical symp-toms 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 carrierswith clinical symptoms are more likely to be reported thanthose without. Thus, a bias in direction of clinically abnormalcases cannot be excluded.

sSMC in Down syndrome casessSMC can also be detected in cases with free trisomy 21 and

Down syndrome (OMIM #190685). Interestingly, at least 25cases with trisomy 21 and an sSMC are reported in the litera-ture. In only three of these the origin of the sSMC was identi-fied. Two were derived from chromosome 15, and one fromchromosome 4 (Heppell-Parton and Waters, 1991; Starke et al.,2003a, cases 10 and 23). The other 22 reports were published inthe pre-FISH era and thus are not informative for this review.However, the Down syndrome phenotype did not seem to bealtered by the presence of an additional sSMC.

sSMC in Turner syndrome casesIn Turner syndrome (OMIM #163950) a small subset of

patients presents with a karyotype 45,X,+mar. 132 case reportsare available in which the sSMC of Turner syndrome werecharacterized 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 chromosomesare preferentially involved in Turner syndrome patients withsSMC; however, we could not confirm this, as we found 73 ver-sus 59 case reports on X chromosome versus Y chromosomeorigin of the sSMC, respectively. Thus, a 1:1 distribution ismost likely. As in Down syndrome, in general no phenotypiccorrelations are reported in connection with an additionalsSMC in Turner syndrome. The exceptions are (1) when thesSMC comes from the Y chromosome the patient’s risk indeveloping either gonadoblastoma or another form of gonadaltumor is enhanced and (2) when the sSMC is derived from theX chromosome and the XIST locus is not present. In the lattercases, more clinical complications appear (Migeon et al.,1993).

sSMC and uniparental disomy (UPD)

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

Ledbetter and Engel (1995), three independent factors areinvolved: (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. More-over, the situation can be complicated by the finding of hetero-disomy combined with isodisomy (e.g. Salafsky et al., 2001).

UPD is without clinical consequences for some chromo-somes (e.g. von Eggeling et al., 2002), but for a few chromo-somes (6, 7, 11, 14, 15 and 20) it can result in abnormality inthe affected individual (Chudoba et al., 1999; Shaffer et al.,2001; Kotzot, 2002). There are only a few systematic studies forUPD in connection with sSMC (James et al., 1995; Anderlid etal., 2001; Starke et al., 2003b). Nonetheless, there are 160 casesin total, which were studied for UPD of the sSMC’s sister-chro-mosomes and a UPD was detected in sixteen (10%). UPD 15 inassociation with Prader-Willi or Angelman syndrome has beendescribed 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 UPD7 (Miyoshi et al., 1999; own unpublished data) was detectedtwice, each. Partial UPD 4 (Starke et al., 2003b, case 10), UPD6 (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 etal., 2003) were all found in single cases. Cases with der(22) syn-drome are excluded here, as they all have, due to their mode offormation, 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 molec-ular cytogenetic characterization, we previously proposed anew sSMC classification (Tables 4 and 5 in Starke et al.,2003b), based on five main classes that are differentiated by thepresence or absence of a nucleolar organizer region (NOR)/cen-tromeric region and a rearrangement of the sSMC. sSMCderived from acrocentric chromosomes (including all minutes,dicentrics, ring chromosomes, and other rearrangements) aresummarized in class 1; in class 2, sSMC derived from all otherchromosomes apart from the acrocentrics are included (as longas they do not comprise any detectable rearrangements); class 3and 4 comprise complex rearranged chromosomes, class 3those which are rearranged with own chromosomal material,class 4 those which are rearranged with others; class 5, finally,includes neocentric sSMC. Furthermore, four subclasses aresuggested that allow for the presence or absence of pericentro-meric euchromatin and/or UPD: class a = neither centromere-near material, nor UPD; class b = no centromere-near material,UPD present; class c = centromere-near material present, noUPD; class d = centromere-near material plus UPD present.


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

Suggestion for the management of prenatally diagnosed sSMC

1. Presence of an sSMC noted: 2. Take parental blood samples for karyotyping (heparinized blood) and UPD test (EDTA-blood). 3. Identify composition and origin of sSMC using appropriate molecular-cytogenetic techniques. 4. 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.

5. Perform microsatellite analysis to exclude an uniparental disomy (UPD) of the sSMC’s sister-chromosomes. 6. Ultrasound scan examination looking for fetal anomalies. 7. Counsel parents regarding likely phenotype. 8. 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.

9. 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, molecularcytogenetics and molecular genetics

Detection of an sSMC is nearly always unexpected by theclinician and more or less an accidental result in cytogenetics.As pointed out previously (Starke et al., 2003b), the origin ofsSMC is almost impossible to establish by routine cytogeneticsalone, whereas FISH methods are highly suited for this. sSMChave been successfully characterized by whole-chromosome-painting (WCP) probes, centromere-specific probes, combinedchromosome microdissection plus reverse painting and FISHapproaches (for a review, see Nietzel et al., 2001) and compara-tive genomic hybridization (e.g. Levy et al., 2002). WCP-FISHapproaches are well suited for the determination of the chromo-somal origin of marker or derivative chromosomes providingthat 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 ofthe short arm of chromosome 17p or more, characterization bythe multicolor banding (MCB) technique is possible (Weise etal., 2002; Starke et al., 2003b). For a fast and easy characteriza-tion of sSMC we recently proposed the centromere-specificmulticolor FISH (cenM-FISH) method (Nietzel et al., 2001).Despite this, analyses of sSMC to detect the presence of euchro-matin to date have been ambiguous and have required furtherclarification. In the recent paper of Starke et al. (2003b), wehave addressed this problem by utilizing a probe-set compris-ing 43 bacterial or yeast artificial chromosome (BAC or YAC,respectively) clones located in the proximal regions of eachhuman chromosome, called subcentromeric multicolor-FISH(subcenM-FISH). We and others (Chudoba et al., 1999; vonEggeling et al., 2002; reviewed in Kotzot, 2002), previously rec-ommended that, after identification of the origin of the SMC,its normal sister-chromosomes should be tested for their paren-tal origin to exclude a possible UPD. UPD can be tested bymolecular genetic approaches, such as microsatellite analysis(Salafsky et al., 2001) or methylation-specific polymerase chainreaction (PCR) (Nietzel et al., 2003) and at the present state of

research, according to our opinion, should be done for everysSMC case in which parental cell material is available.

A possible strategy for dealing with sSMC cases is summa-rized in Table 2.

Towards a clinical correlation of sSMC

Great advances were achieved especially in the recent yearsboth in sSMC characterization and insight into their clinicalimpact. Between 1961 and the end of the 1970’s no specificclinical syndrome was characterized among the sSMC cases.The der(22) and the cat eye syndromes (CES) were the first tobe identified (Fraccaro et al., 1980; Schinzel et al., 1981), fol-lowed by the Pallister-Killian Syndrome (PKS) (Peltomaki etal., 1987) and the i(18p) syndrome. The latter was unambig-uously confirmed to be due to partial tetrasomy 18p by applica-tion of radioactive in situ hybridization in 1990 (Callen et al.,1990). The introduction of UPD studies in sSMC cases was thenext milestone (James et al., 1995). When Crolla (1998) pub-lished the first major review on sSMC, it was additionally clearthat the inverted duplicated chromosomes derived from chro-mosome 15 constituted a specific subgroup and, as suggested in1993 (Robinson et al., 1993a), the clinical severity of cases withinv dup(15) is associated with the presence and dosage of thePrader-Willi/Angelman syndrome critical region (OMIM#176270, #105830) rather than with differences in the extent ofthe duplicated segment (Nietzel et al., 2003). During the next10 years (starting from 1993) many sSMC cases were studied byvarious approaches. But up to the description of the subcenMapproach (Starke et al., 2003b), no considerable progress con-cerning the problem of centromere-associated proximal triso-my and phenotype-associated risk evaluation was done. Thus,up to the present time approximately 30% of sSMC still lack aclinical correlation (see also Fig. 4).

Recently we reported 35 cases of sSMC which were compre-hensively studied for their euchromatic content and, wherepossible, as well for presence of UPD of the sister chromosomes(Starke et al., 2003b). Based on this study and from data from


the literature we were able to provide a first step toward theidentification of pericentromeric disease-related genes. AllsSMC without euchromatic content and no UPD turned out tobe harmless. Psychomotor or mental retardation and/or dys-morphic signs could be observed in connection with an sSMCand the presence of additional euchromatic content derivedfrom chromosomes 1p, 1q, 2p, 7q, 9p, or 12q. Imbalances inthe juxtacentromeric region of 2q, 3p, 4q, 5q, 7p, 8p, 17p, 18p,19p/19q, and 22q (excluding the cat eye syndrome criticalregion in 22q11.2→3) were without clinical consequences. Thestudy of Starke et al. (2003b) has revealed clinical correlationsin connection with sSMC formation and partial proximal tri-somies for 18 of the 43 centromere-near regions of the human

genome. However, these data are based in parts on single casesand need to be complemented by further studies (see as wellTable 3 in Starke et al., 2003b).

This review combined with the highly informative recentlydescribed molecular cytogenetic approaches (Nietzel et al.,2001; Trifonov et al., 2003; Starke et al., 2001, 2003b) should itmake more feasible for the clinician to do genetic counseling ofparents expecting children with de novo sSMC.

Acknowledgements

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

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