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- BASIC INFORMATION ON sSMC -
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Here some
basic information on sSMC in general is
summarized: It is explained what sSMC are,
what effects they have, when the first sSMC
was seen, what happens if genetic relevant
material (euchromatin) is present on the
sSMC, what is known about mosaicism in sSMC,
what is known on sSMC in connection with
uniparental disomy (UPD), which synonyms are
used for sSMC, in which frequencies sSMC
appear, and what is known on the way of
their formation.
A summarizing talk from summer 2019 entitled "An update on small supernumerary marker chromosomes (sSMC)" is also available here. |
sSMC "can be defined as small structurally abnormal chromosomes that occur in addition to the normal 46 chromosomes" {80}
"The term (small) 'supernumerary marker chromosome' (=sSMC) has been used to refer to any unidentifiable marker chromosome and clearly covers a diverse range of cytogenetic abnormalities" {3}
"Such an 'accessory' chromosome of unknown origin is referred as a marker chromosome (mar), using the standardized human chromosome nomenclature (Paris Conference 1971), and they comprise a mixed collection of structurally rearranged chromosome regions" {2}.
Up to 2004 it was still worth what was stated in 1987 {14-15} and 1992 {16; 42}, respectively:
"For humans there are at present no uniform criteria that enable precise distinction of supernumerary chromosomes from other extra structurally abnormal chromosome" {14}
Several attempts have been made to correlate specific marker chromosomes with a clinical picture. This has resulted in the description of a few specific syndromes, e.g. i(18p)-syndrome, i(9p)-syndrome, the Pallister-Killian syndrome = i(12p)-syndrome and the cat-eye syndrome. However, most markers have not been fully characterized {16; 44}.
I.e. sSMC are a morphologically heterogeneous group of structural abnormal chromosomes:
different types of inverted duplicated chromosomes, minute chromosomes and ring chromosomes can be detected (see Figure below).
Thus, the description of sSMC as ‘markers’, makes sense and should be maintained, even after their identification by molecular cytogenetics.
We suggested the following cytogenetic definition of sSMC {see as well 120-121}
sSMC are structurally abnormal chromosomes that cannot be identified unambiguously by conventional banding cytogenetics alone, and are equal in size or smaller than a chromosome 20 of the same metaphase spread (see Fig. 1). sSMC can be present 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 or ring chromosome formation. In contrast, a SMC larger than chromosome 20 usually can be identified based on chromosome-banding. Even though cases with isochromosome 5p, 8p and 9p are not included in the group of sSMC according to that definition, they are included in this page.
What else?
At least minute sSMC evolve by trisomic rescue as recently shown in two cases {112-113}.
If among sSMC B-chromosomes are hidden is discussed in the literature {162} - also how B-chromosomes behave in general {199}. Also there are, like human sSMC(15) being candidtae for human B-chrs., sicentric B-chrs. e.g. in Maize {201}.
An acrocentric inv dup shaped sSMC was found in an Asian elefant family {200}.
Also their way of formation may be related to Howel Joly Body formation {164}
sSMC might be helpful as gene vectors in future {171}
sSMC can be found as de novo events in tumor cells, but constitutional, inherited or de novo sSMC do not cause cancer! {see this web page chromosme-specific sites - sSMC found in tumors}
sSMC should not be mixed up with double minutes (cancer associated extrachromosomal double dot like DNA containing mainly oncogene-amplification), or
also not with 'markers' as described by Dr. Hit Kishore Goswami, Bhopal, India in several papers {193-196}.
In 1961 Ilberry et al. {28} describe a 2 year old boy with epicanthic fold, slightly protuberant tongue who had a karyotype 47,XY,+mar[53]/46,XY[16]de novo.
The sSMC was a "centric particle" of about the same size as 17p.
This paper was not well-recognized and thus, the work of Froland et al. {8} is often mentioned as first description of sSMC.
The latter describe a boy with various congenital defects and a karyotype 47,XY,+mar; the sSMC is metacentric and of comparable size as #21 - and turned out to be a tetrasomy 18p {72}.
However, the case reported by Froland et al. (1963) was indeed only the third described sSMC-case, as in 1962 there was an additional report of Ellis et al. {106}.
Euchromatin is genetic relevant
material and to be distigished from heterochromatin.
The latter does not include any genes.
sSMC may consist of both: eu- and heterochromatin.
Strikingly euchromatin can be present on an sSMC and must not cause any harm in the carrier.
It depends which exact genetic imbalance was induced. Thus, a detailed sSMC characterization is necessary esp. in prenatal cases!!
Euchromatin was / can be detected or excluded on sSMC by different methods:
Replication banding {49}
C-bands {58-59}DA/DAPI staining for characterization of chromosome 15 - however, its abilities have been questioned {60-63; 75}
Rx-FISH {50}
microdissection and reverse painting (e.g. {51})
FISH using locus specific probes (e.g. {52})
association of sSMC with centromeric regions - the more heterochromatin they consist of the better they associate {82-87}
array-CGH studies (e.g. {173})
NGS (e.g. {184})
sSMC may consist of both: eu- and heterochromatin.
Strikingly euchromatin can be present on an sSMC and must not cause any harm in the carrier.
It depends which exact genetic imbalance was induced. Thus, a detailed sSMC characterization is necessary esp. in prenatal cases!!
Euchromatin was / can be detected or excluded on sSMC by different methods:
Replication banding {49}
C-bands {58-59}DA/DAPI staining for characterization of chromosome 15 - however, its abilities have been questioned {60-63; 75}
Rx-FISH {50}
microdissection and reverse painting (e.g. {51})
FISH using locus specific probes (e.g. {52})
association of sSMC with centromeric regions - the more heterochromatin they consist of the better they associate {82-87}
array-CGH studies (e.g. {173})
NGS (e.g. {184})
Mosaicism in sSMC carriers is present in slightly over 50% of the cases {172}.
Interestingly, non-acrocentric derived sSMC show much more frequently mosaicism than acrocentric ones. sSMC can be present in different mosaic rates, which may go below 5% of the studied cells. Also cryptic mosaicism can be present and mosaics may be differently expressed in different tissues of the body. Even though in the overwhelming majority of the cases somatic sSMC mosaicism has no direct clinical effects, there are also cases with altered clinical outcomes due to mosaicism. Also clinically important is the fact that a de novo sSMC, even present in mosaic, may be a hint on uniparental disomy (UPD). {172}
Mosaicism in phenotypically normal sSMC carriers: 61.9% {42} or 52.3% {43}
Mosaicism in phenotypically abnormal sSMC carriers: 56.6% {42} or 56.3% {43}
Mosaicism in a fetus with sSMC showing a big variation of cells with and without sSMC (see table below).
Thus, cultured amniocytic fluid, chorion or fetal blood is not necessarily representative for the fetus as a whole. {165}
| Studied
tissue (interphase) |
sSMC present in % |
| amnion (after long
term culture - metaphases) |
13 |
| placenta | 19 |
| thymus | 20 |
| B-cells (EBV cell
culture - metaphases) |
21 |
| spleen | 40 |
| liver | 41 |
| adrenal gland | 42 |
| aorta | 44 |
| brain | 45 |
| umbilical cord |
51 |
| kidney | 55 |
| lung | 56 |
| heart | 62 |
Development of mosaicism during lifetime:
In {88} it was postulated that the percentage of cells with sSMC decrease during lifetime - especially in sSRC cases.
In {64} a case is described with a sSRC with a karyotype 48,XX,+rx2/47,XX+r/47,XX,+r(doublering)/46,XX; here at birth a mosaicism of 0%/77.9%/2.3%/19.8% was described; at 5.5y the patient had a mosaicism of 0.9%/46.6%/4.4%/49.1%. This confirms that theory.
In {96} the authors describe a case with a larger supernumerary marker chromosome which disappeared during the first 6 months of lifetime completely from peripheral blood. It was present first in 6/22 cells (day 12) and declined over 3/57 (day 23) and 2/70 (month 9) to 0/100 (16 months and 2 years).
In parts there are confusing examples for mosaicism:
- Ref. {45}, cases H and I: sSMC
12 in 35% of the cells in a phenotypically normal
father and in 100% of son with neurological
disorder and facial anomalies. - Similar case is
in Ref. {46} case 14;
- Ref. {81} describes a family
with different degrees of cells with the
Cat-Eye-Syndrome (CES) marker; a child with CES
has the sSMC in 100% while mother and two sisters
have the sSMC in only 1-60% of the cells; the
latter are less or minimal affected. Additionally,
the sSMC is present in at least 5 variants in the
mother, which look like degraded CES markers.
- Ref. {47} shows similar grades
of mosaicism in two generations but variations in
the clinical outcome.
- Ref. {45} cases E and F plus B and C: great variations in mosaicism but no phenotypic consequences.
Small supernumerary maker chromosomes (sSMC) and uniparental disomy (UPD) is rare, combination of both are rarely encountered. Accordingly only 46 sSMC cases with UPD are reported. Irrespective of its rareness, UPD has to be considered especially in prenatal cases with sSMC. Here we reviewed all sSMC cases with UPD (sSMCU+) and compared them to sSMC without UPD (sSMCU-).
It resulted in following correlations:
i) every sSMC, irrespective of its chromosomal origin maybe principally connected with UPD,
ii) mixed hetero- and iso UPD (hUPD/iUPD) can be observed most oftenly in sSMCU+ cases followed by complete iUPD, complete hUPD and segmental iUPD.
iii) UPD of chromosomes #6, #7, #14, #15, #16 and #20 are most often reported in sSMCU+,
iv) maternal UPD was approximately nine times more frequent than paternal,
v) if mosaic with a normal cell line, acrocentric derived sSMC had three times higher chances of occurence than its corrosponding non-mosaic sSMC cases ,
vi) UPD in connection with a parentally inherited sSMC is, if existent at all, a rare event,
vii) The gender type and shape of sSMC had no effect on UPD formation.
Overall, sSMCU+ cases may have a story to tell about ‘chromosome number control mechanisms’ in early embryogenesis. {174}
Unfortunately sSMC are reported in
the literature under a lot of synonyms, which
makes finding of all relevant reports not that
easy.
Here a collection of designations given during the last years:
Here a collection of designations given during the last years:
|
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Frequency of sSMC in newborn
Overall, in newborn cases the rate is 0.044% {157}
some examples from literature: 0.026% (16 in 59952 newborn infants) {1 here are taken together: 17-18, 22-27}
0.024% ( 4 in 16395 newborn infants) {2}
0.123% ( 8 in 6500 newborn infants) {3}
0.040% ( 3 in 7536 newborn infants) {4-6 taken together according to 3}
0.054% ( 6 in 11148 newborn infants) {7}
0.069% (24 in 34910 newborn infants) {19; 62}
0.027% ( 4 in 14835 newborn infants) {98}
0.219% ( 4 in 1830 newborn infants) {125}
0.000% ( 0 in 930 newborn infants) {126}
0.027% ( 1 in 3665 newborn infants) {143}
According to {142} sSMC occur - in 27.7% of aborted fetuses (9/46 cases) but only - in 9.2% (7/76 cases) of term births
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Frequency of sSMC in prenatal cases
Overall, in prenatal cases the rate is 0.075% {157}
In Ref. {153} 20 sSMC were found in 15792 prenatal cases.
The cases were studied due to
+ advanced maternal age [54.16%],
+ increased risk acc. to triple test [19.27%],
+ pathologic ultrasound finding [14.26%], or others
In Ref {177} 8 sSMC were found in 10125 prenatal cases in Turkey.
In Ref {187} 59 sSMC were found in 68087 prenatal cases in Taiwan.
According to {16} the higher rate of cases with sSMC in prenatal compared to newborn can be due to
(1) the bias caused by the maternal age effect in prenatal series,
(2) the fact that prenatal diagnosis is sometimes performed due to known or suspected fetal pathology, and/or
(3) severely affected fetuses may result in miscarriages and will therefore not be included among newborns.
According to {142} - a study done in 1997
+ ~50% of pregnancies with sSMC were terminated;
+ 4.4% of the remaining pregnancies ended with stillbirth or spontaneous abortion;
+ the rest of the children wer born clinically normal.
According to {116} - a study done in 2004
+ 20% of pregnancies with cytogenetic aberrations (419 cases) are terminated;
+ 31% of the cases with de novo sSMC are selectively terminated!
According to {166} - a study done in 2003:
+ in 7/7 inherited sSMC pregnancy continued in 8/17 pregnancies with de novo sSMC pregnancy was terminated
+ i.e. ~50% were terminated in this Italian study
According to {158} an sSMC was present in 1/13 pregnancies with exomphalos.
According to {159} an sSMC was present in 1/70 pregnancies with cleft palate.
In {181} sSMC found in infertile are reviewed.
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Frequency of sSMC in mentally retarded
Overall, in mentally retarded patients the rate is 0.288% {157}
one single center study found a rate of 0.118%
(in 32,930 patients karyotyped in the Belgium center for Human Genetics between 1966 and 1981) {48}
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Frequency of sSMC subfertile people
Overall, in sub fertile people the rate for male and female together is 0.125% {157}
but it differs with 0.165% in male versus 0.022% in female.
In Ref. 69 it is suggested that sSMC could disrupt human spermatogenesis
In {142} the influence of sSMC on non-disjunction is discussed.
644 cases with autosomal sSMC collected in that page by 13.Nov. 2004
were specified by their gender: 322/644 where male an 322/644 female.
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Frequency of sSMC if sSMC is de novo
Overall, 70% of sSMC are de novo {157}
77% of sSMC are de novo (172 in 241 cases) - 16% maternally, 7% paternally inherited {151}.
According to {53; 94} no discernibly increase risk for fetal abnormalities if sSMC is also present in a phenotypically normal parent.
According to this page (12/06/2005) 918/1872 de novo; 111/1872 inherited 943/1872 no information available;
i.e. de novo → 89.2%; inherited → 10,8%.
This reflects the ascertainment bias present in the sSMC cases collectable on this page.
But: 66/111 sSMC cases are of maternal origin;
39/111 are of paternal origin
6 familial → concordance with {151}
0.125% (3 in 2,400 adult healthy persons; 2 of the 3 cases were familial) had a de novo sSMC {29}
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Frequency of sSMC if sSMC is acrocentric derived
Overall, 70% of sSMC are acrocentric derived {157}
86% (i.e. in 38 of 44 cases) {2}
81% (i.e. in 17 of 20 cases) {16}
45% with satellites (i.e. 14 of 31 cases) {16}
68% (i.e. in 26 of 38 cases) {46}
among mentally retarded 50% with satellites (i.e. 27 of 54 cases) {91}
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Frequency of sSMC of one single UK facility (Dr. Crollas group {147}) 137 patients with sSMC
37% with abnormal phenotype
7% couples with reproductive difficulties
47% antenatal diagnosis
9% miscellaneous
59% mosaics
41% no mosaics
70% de novo
19% maternal origin
11% paternal origin (of 109 of the cases)
36% derived from non-acrocentrics (of 112 cases studied by FISH)
35% derived from #15
9% from #22 sSMC(15) appearance seems to be associated with advanced maternal age.
In China in 74,266 samples (pre and postnatals) 75 sSMC (0,1%) were found {189}
in a very mixed group of patients.
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Frequency of sSMC if ring chromosome shaped
10% (i.e. 3 of 31 cases) {16}
60% of case with sSRC are associated with an abnormal phenotype {77}
Apart from the shape a ring is characterized by: "the detection of anaphase bridges and micronuclei in the monolayer fibroblast culture" {64}
sSRC per definition do not have telomeric sequences {78; 79}
Ring chromosomes can also have telomeric sequences {169}
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Overall, little is known on sSMC formation.
What we know is:
- sSMC may form from each chromosome (see this collection)
- inherited sSMC mainly derive from maternal origin {175}
- de novo sSMC often form by trisomic rescue {112-113}
- sSMC formation seems to be different according to sSMC shape (see below)
- in {183} a rolling circle mechansism is suggested
sSMC-formation in:
| inverted duplication shape |
ring
shape |
centric
minute shape |
| neocentrics |
complex |
multiple |
| discontinous |
McClintock |
Pseudo-McClintock |
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inverted duplication shape
For formation of inv dup shaped sSMC several models were proposed {1-7}. The most plausible of those is that an intra- {8} or interchromosomal U-type exchange of homologous chromosomes takes place, resulting from a crossover mistake of chromatids during meiosis {1}. U-type exchange seems to be a more general mechanism of isochromosome formation, which was found in tumor cells, as well {9-10}.
A mechanism resembling {8} or being identical to intrachromosomal U-type exchange was proven yet for neocentric inv dup formation, where it could even be the primary mechanism of formation {8;11}. Also, this kimd of formation must take place in all cases with inv dup sSMC derived from the Y-chromosome in Turner-syndrome karyotype carriers {12}.
Due to different heteromorphisms present on the two cetromeric and/or pericentric regions of some reported centric inv dup shaped sSMC, interchromosomal origin was proven exemplarily there {13-14}. Also evidence was provided that this kind of U-type exchange may predominantly happen in maternal meiosis {10;13}. It was postulated that similar breakpoints in 15q are involved not only in centric inv dup shaped sSMC formation, but also in other rearrangements {16}.
N.B.: Inverted duplicated shaped sSMC can also form after ‘ring opening’ and inverted duplication of a centric minute.
For present knowledge on centromeric activity in dicentric sSMC see {15}.
Model of formation
Inverted duplicated shaped sSMC form by U-type exchange mechanism. b = break; n = neocentromere formation can happen.
References for section inv dup formation
- Schreck RR,
Breg WR, Erlanger BF, Miller OJ.
Preferential derivation of abnormal human G-group-like chromosomes from chromosome 15.
Hum Genet. 1977 Apr 7;36(1):1-12.
- Jones GH, Brumpton RJ.
Sister and non-sister chromatid U-type exchanges in rye meisois.
Chromosoma 1971, 33: 115-128.
- Brandham PE.
Stabilised breakage of a duplication chromosome segment in Aloe.
Chromosoma 1975, 51: 369-378.
- Van Dyke DL,
Weiss L, Logan M, Pai GS.
The origin and behavior of two isodicentric bisatellited chromosomes.
Am J Hum Genet. 1977 May;29(3):294-300
- Ing PS,
Lubinsky MS, Smith SD, Golden E, Sanger WG,
Duncan AM.
Cat-eye syndrome with different marker chromosomes in a mother and daughter.
Am J Med Genet. 1987 Mar;26(3):621-628.
- Armendares S,
Buentello L, Cuevas-Sosa A, Cantu-Garza JM.
Familial extra centric bisatellited chromosome.
Cytogenetics. 1969;8(3):177-186.
- Dewald GW.
Isodicentric X chromosomes in humans: origin, segregation behaviour, and replication band patterns.
In: Sandberg AA (ed.) Cytogenetics of the mammalian X chromosome, part A. Liss, New York, 1983, pp 405-426.
- Murmann AE,
Conrad DF, Mashek H, Curtis CA, Nicolae RI,
Ober C, Schwartz S.
Inverted duplications on acentric markers: mechanism of formation.
Hum Mol Genet. 2009 Jun 15;18(12):2241-2256.
- Mukherjee AB,
Murty VV, Rodriguez E, Reuter VE, Bosl GJ,
Chaganti RS.
Detection and analysis of origin of i(12p), a diagnostic marker of human male germ cell tumors, by fluorescence in situ hybridization.
Genes Chromosomes Cancer. 1991 Jul;3(4):300-307.
- Wang NJ,
Parokonny AS, Thatcher KN, Driscoll J, Malone
BM, Dorrani N, Sigman M, LaSalle JM, Schanen
NC.
Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15.
BMC Genet. 2008 Jan 4;9:2.
- Sheth F, Ewers
E, Kosyakova N, Weise A, Sheth J, Patil S,
Ziegler M, Liehr T.
A neocentric isochromosome Yp present as additional small supernumerary marker chromosome--evidence against U-type exchange mechanism?
Cytogenet Genome Res. 2009;125(2):115-116.
- Liehr T,
Mrasek K, Hinreiner S, Reich D, Ewers E,
Bartels I, Seidel J, Emmanuil N, Petesen M,
Polityko A, Dufke A, Iourov I, Trifonov V,
Vermeesch J, Weise A.
Small supernumerary marker chromosomes (sSMC) in patients with a 45,X/46,X,+mar karyotype - 17 new cases and a review of the literature.
Sex Dev. 2007;1(6):353-362.
- Magenis RE,
Sheehy RR, Brown MG, McDermid HE, White BN,
Zonana J, Weleber R.
Parental origin of the extra chromosome in the cat eye syndrome: evidence from heteromorphism and in situ hybridization analysis.
Am J Med Genet. 1988 Jan;29(1):9-19.
- Liehr T,
Pfeiffer RA, Trautmann U.
Typical and partial cat eye syndrome: identification of the marker chromosome by FISH.
Clin Genet. 1992 Aug;42(2):91-96.
- Ewers E, Yoda
K, Hamid AB, Weise A, Manvelyan M, Liehr T.
Centromere activity in dicentric small supernumerary marker chromosomes.
Chromosome Res. 2010 Jul;18(5):555-562.
- Rossi E,
Giorda R, Bonaglia MC, Candia SD, Grechi E,
Franzese A, Soli F, Rivieri F, Patricelli
MG, Saccilotto D, Bonfante A, Giglio S, Beri
S, Rocchi M, Zuffardi O.
De novo unbalanced translocations in Prader-Willi and Angelman syndrome might be the reciprocal product of inv dup(15)s.
PLoS One. 2012;7(6):e39180.
ring shape
Several possibilities how ring shaped sSMC may evolve were proposed. First, such kind of sSMC can be formed in association with a deletion of a part of the chromosome. This leads to a balanced situation in the carrier and is known as McClintock-mechanism {1}. Clinical problems only arise if exclusively the sSMC or the derivative chromsome from which the sSMC was cut out are passed to a carrier’s child, as then a chromosomal imbalance - either partial trisomy or partial monosomy - is present. In such ring shaped sSMC parts of the centromere can be included, leaving two centric chromosome fragments one of which forms a small ring, or a neocentromere is formed within the ring shaped sSMC {2} or the derivative.
Second, ring formation has been proposed in connection with an inverted duplication as due to a U-type reunion between broken sister chromatids {3}. This kind of ring was only rarely reported for sSMC yet, and if so it was observed in ‘larger’ sSMC or SMC {4}. This might be connected with steric problems this mechanism may face in sSMC.
Third, for the overwhelming majority of ring shaped sSMC a ring formation starting from a centric minute is suggested, which during karyotypic evolution acquires the ring shape, maybe to become more stable {5}.
N.B.: The formation of double ringsis well known and frequently observed. It is thought to be due to a sister chromatid exchange with a normal centromere division {6}.
A ring shaped sSMC can form as follows:
1) In a balanced karyotype parts of the sSMC’s sister-chromosome are excised and stabilized by ring formation (McClintock-mechanism).
Either the ring shaped sSMC and the derivative chromosome share the centromeric region (1-1), or a neocentromere (n) is formed on sSMC (1-2) or the derivative (not depicted).
2) Ring formation can be due to an intrachromosomal U-type exchange.
3) A ring shaped sSMC can evolve from a centric minute shaped sSMC.
References for section ring formation
- Baldwin
EL, May LF, Justice AN, Martin CL, Ledbetter
DH.
Mechanisms and consequences of small supernumerary marker chromosomes: from Barbara McClintock to modern genetic-counseling issues.
Am J Hum Genet. 2008 Feb;82(2):398-410.
- Liehr T,
Utine GE, Trautmann U, Rauch A, Kuechler A,
Pietrzak J, Bocian E, Kosyakova N, Mrasek K,
Boduroglu K, Weise A, Aktas D.
Neocentric small supernumerary marker chromosomes (sSMC)--three more cases and review of the literature.
Cytogenet Genome Res. 2007;118(1):31-7. Review. Erratum in: Cytogenet Genome Res. 2007 Dec;119(1-2):170. Pietracz, J [corrected to Pietrzak, J].
- Michalski
K, Rauer M, Williamson N, Perszyk A, Hoo JJ.
Identification, counselling, and outcome of two cases of prenatally diagnosed supernumerary small ring chromosomes.
Am J Med Genet. 1993 Apr 1;46(1):88-94.
- Starke
H, Seidel J, Henn W, Reichardt S, Volleth M,
Stumm M, Behrend C, Sandig KR, Kelbova C,
Senger G, Albrecht B, Hansmann I, Heller A,
Claussen U, Liehr T.
Homologous sequences at human chromosome 9 bands p12 and q13-21.1 are involved in different patterns of pericentric rearrangements.
Eur J Hum Genet. 2002 Dec;10(12):790-800.
- Liehr
T, Claussen U, Starke H.
Small supernumerary marker chromosomes (sSMC) in humans.
Cytogenet Genome Res. 2004;107(1-2):55-67.
- Ramírez-Dueñas
ML, González GJ.
fra(1) (p11), fra(1) (q22) and r(1) (p11q22) in a retarded girl.
Ann Genet. 1992;35(3):178-82.
centric minute shape
Different mechanisms of centric minute sSMC formation, including trisomic and monosomic rescue, post fertilization errors and gamete complementation, have been proposed in literature. Mosaicism resulting in one cell line with sSMC and one with a trisomy provided evidence for functional trisomic rescue as a real existing mechanism {1-2}. In implanted embryos the rate of trisomies was estimated to be 16% {3}, however, no data is available how many of them undergo trisomic rescue events.
Up to present no pathways or enzymes involved in the processes of trisomic or monosomic rescue formation are known.
N.B.: Centric minute shaped sSMC can also form by ‘ring opening’.
Also formation of a centric minute shaped sSMC was reported together with partial deletion due to dicentric intermediate {4}.
References for section centric minute formation
- Bartels I,
Schlueter G, Liehr T, von Eggeling F, Starke
H, Glaubitz R, Burfeind P.
Supernumerary small marker chromosome (SMC) and uniparental disomy 22 in a child with confined placental mosaicism of trisomy 22: trisomy rescue due to marker chromosome formation.
Cytogenet Genome Res. 2003;101(2):103-105.
- Stefanou EG,
Crocker M.
A chromosome 21-derived minute marker in a mosaic trisomy 21 background: Implications for risk assessments in marker chromosome cases.
Am J Med Genet. 2004 Jun 1;127A(2):191-193.
- Farfalli VI,
Magli MC, Ferraretti AP, Gianaroli L.
Role of aneuploidy on embryo implantation.
Gynecol Obstet Invest. 2007;64(3):161-165.
- Pedurupillay
CR, Misceo D, Gamage TH, Dissanayake VH,
Frengen E.
Post-zygotic breakage of a dicentric chromosome results in mosaicism for a telocentric 9p marker chromosome in a boy with developmental delay.
Gene. 2014 Jan 1;533(1):403-410.
for as side effect of inv dup sSMC formation see here and {1}.
for as ring chromosomes due to McClintock mechanism see here.
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neocentric sSMC
Really, mainly inv dup and ring shaped neocentric sSMC are reported {1}. However, there are also hints on centric minute shaphed neocentrics.
References for neocentric formation
- Rossi E,
Giorda R, Bonaglia MC, Candia SD, Grechi E,
Franzese A, Soli F, Rivieri F, Patricelli
MG, Saccilotto D, Bonfante A, Giglio S, Beri
S, Rocchi M, Zuffardi O.
De novo unbalanced translocations in Prader-Willi and Angelman syndrome might be the reciprocal product of inv dup(15)s.
PLoS One. 2012;7(6):e39180.
complex sSMC
Complex rearranged sSMC {1 , 3} are only identifiable as such after molecular (cytogenetic) analysis. In cytogenetic analysis they look like centric minute, ring or inverted duplicated shaped. The majority of complex rearranged sSMC are constituted by the cases with Emanuel syndrome {2}. The carriers of this special derivative chromosome #22 (der(22)t(11;22)(q23;q11)) normally inherit it from a parent who has a balanced translocation t(11;22)(q23;q11). A person or better an embryo having a karyotype 46,XN,der(22)(11;22)(q23;q11) is not viable. Thus, patients with ES have had either to double their only chromosome #22 during early embryogenesis, or gamete complementation must have taken place.
Complex sSMC besides ES (for review see {1}) either derive from one single, from two, or even from three different chromosomes. Models how they form are not available yet, even though copy number variant regions are thought to be causative for rearrangements.
In cases when a complex sSMC may result from a parental balanced translocation some insights into their meiotic behaviour are available {4}.
References for complex sSMC formation
- Trifonov V,
Fluri S, Binkert F, Nandini A, Anderson J,
Rodriguez L, Gross M, Kosyakova N, Mkrtchyan
H, Ewers E, Reich D, Weise A, Liehr T.
Complex rearranged small supernumerary marker chromosomes (sSMC), three new cases; evidence for an underestimated entity?
Mol Cytogenet. 2008 Apr 15;1:6. - Carter MT,
St Pierre SA, Zackai EH, Emanuel BS, Boycott
KM.
Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals.
Am J Med Genet A. 2009 Aug;149A(8):1712-21. - Liehr
T, Cirkovic S, Lalic T, Guc-Scekic M, de Almeida
C, Weimer J, Iourov I, Melaragno MI, Guilherme RS,
Stefanou EG, Aktas D, Kreskowski K, Klein E,
Ziegler M, Kosyakova N, Volleth M, Hamid AB.
Complex small supernumerary marker chromosomes - an update.
Mol Cytogenet. 2013 Oct 31;6:46. - Anton
E, Vidal F, Blanco J.
Reciprocal translocations: tracing their meiotic behavior.
Genet Med. 2008 Oct;10(10):730-8.
multiple sSMC
Multiple sSMC derive from a different chromosomal subset as single sSMC. Besides, they have also another distribution of shapes as centric sSMC in general. While in single sSMC there is a difference in shape distribution distinguishing acrocentric from non-acrocentric derived ones, this is not the case in multiple sSMC. Also, centric minute shaped ones are most frequent in multiple sSMC followed by ring and inverted duplication. Thus, Beverstock et al. (2003) {1} suggested correctly that the formation of multiple sSMC of different chromosomal origin is based on some other mechanism as those discussed above for single sSMC. Daniel and Malafiej (2003) {2} proposed multiple sSMC may originate from transfection of chromosomes into the zygote derived from one or more superfluous haploid pronuclei that would normally be degraded. Also, rescue of a triploid zygote could be the reason for multiple sSMC. However, no studies are available supporting any of these ideas.
References for multiple sSMC
- Beverstock
GC, Bezrookove V, Mollevanger P, van de Kamp
JJ, Pearson P, Kouwenberg JM, Rosenberg C.
Multiple supernumerary ring chromosomes of different origin in a patient: a clinical report and review of the literature.
Am J Med Genet A. 2003 Oct 1;122A(2):168-173.
- Daniel A,
Malafiej P.
A series of supernumerary small ring marker autosomes identified by FISH with chromosome probe arrays and literature review excluding chromosome 15.
Am J Med Genet A. 2003 Mar 15;117A(3):212-22.
Discontinous
Discontinous sSMC are known since ~2000s, but where suggested to be rather exceptions than the rule.
Since recognition that chromothripsis maybe involved in sSMC formation more discontinous sSMC are recogniced and reported,
Still it is not clear yet what is the exact percentage of such sSMC {1-3}.
References for discontinous sSMC
- Liehr
T.
Chromothripsis detectable in small supernumerary marker chromosomes (sSMC). Using fluorescence in situ hybridization (FISH).
Methods Mol Biol. 2018;1769:79-84. - Kurtas NE, Xumerle L,
Leonardelli L, Delledonne M, Brusco A,
Chrzanowska K, Schinzel A, Larizza D,
Guerneri S, Natacci F, Bonaglia MC, Reho
P, Manolakos E, Mattina T, Soli F,
Provenzano A, Al-Rikabi AH, Errichiello
E, Nazaryan-Petersen L, Giglio S,
Tommerup N, Liehr T, Zuffardi O.
Small supernumerary marker chromosomes: A legacy of trisomy rescue?
Hum Mutat. 2019 Feb;40(2):193-200.
- Al-Rikabi
ABH, Pekova S, Fan X, Jančušková T, Liehr
T.
Small supernumerary marker chromosome may provide information on dosage-insensitive pericentric regions in human.
Curr Genomics. 2018 Apr;19(3):192-199.
- Grochowski CM, Gu S,
Yuan B, Tcw J, Brennand KJ,
Sebat J, Malhotra D, McCarthy
S, Rudolph U, Lindstrand A,
Chong Z, Levy DL, Lupski JR,
Carvalho CMB.
Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes.
Hum Mutat. 2018 Jul;39(7):939-946.
McClintock
"In one of her seminal contributions Barbara McClintock describes the mechanism leading to the formation of ring/deleted chromosomes in maize and the aberrant mitotic behaviour leading to 'variable mutant characteristics'. This mechanism, a break within the centromere together with a break in either the long or the short arm, creating a small ring, has been called "centromere misdivision"; these authors propose that this be referred to as "the McClintock mechanism". McClintock also describes pachytene configurations in microsporocytes, showing that although the normal, deleted and ring chromosomes may synapse, the ring is also seen with the centromeric region attached to a non-homologous bivalent."
(cited from Mantzouratou et al., Molecular Cytogenetics 2009, 2:3) - see also here
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Pseudo-McClintock
It turned out that similar to McClintock mechanism with ring chromosome formation, there are cases which seem to evolve by a related mechnaism, called pseudo-McClintock mechansim.
