tl_files/tiny_templates/Bilder TL/Header-sSMC.jpg

- sSMC -

BASICS

 

sSMC-formation

 

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)

 

sSMC-formation in:
- inverted duplication shape
- ring shape
- centric minute shape
- neocentrics
- complex
- multiple

 

References


 


 

 

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 centromeric 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

 

tl_files/tiny_templates/Bilder TL/sSMC form inv.jpg

Inverted duplicated shaped sSMC form by U-type exchange mechanism. b = break; n = neocentromere formation can happen. 


References for section inv dup formation

  1. 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.
  2. Jones GH, Brumpton RJ.
    Sister and non-sister chromatid U-type exchanges in rye meisois.
    Chromosoma 1971, 33: 115-128.
  3. Brandham PE.
    Stabilised breakage of a duplication chromosome segment in Aloe.
    Chromosoma 1975, 51: 369-378.
  4. 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
  5. 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.
  6. Armendares S, Buentello L, Cuevas-Sosa A, Cantu-Garza JM.
    Familial extra centric bisatellited chromosome.
    Cytogenetics. 1969;8(3):177-186.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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:

tl_files/tiny_templates/Bilder TL/sSMC form rin.jpg

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

 

  1. 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.
  2. 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].
  3. 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.
  4. 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.
  5. Liehr T, Claussen U, Starke H.
    Small supernumerary marker chromosomes (sSMC) in humans.
    Cytogenet Genome Res. 2004;107(1-2):55-67.
  6. 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 presnet 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

 

  1. 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.
  2. 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.
  3. Farfalli VI, Magli MC, Ferraretti AP, Gianaroli L.
    Role of aneuploidy on embryo implantation.
    Gynecol Obstet Invest. 2007;64(3):161-165.

  4. 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.

 


 


 

 

 

neocentrics

At present neocentric sSMC are thought to develop as side effect of inv dup sSMC formation see here and {1}.
or as ring chromosomes due to McClintock mechanism see here.

 

Really, mainly inv dup and ring shaped neocentric sSMC are reported. Howeve, there are also hints on centric minute shaphed neocentrics.

 


References for neocentric formation

  1. 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

Complex rearranged sSMC {1} 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)t(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.

 


References for complex sSMC formation

 

  1. 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.
  2. 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.

 


 


multiple

 

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

  1. 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.
  2. 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.