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

- sSMC -

BASICS

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.



What are sSMC?

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).

tl_files/tiny_templates/Bilder TL/ssmc-shape.jpg

Thus, the description of sSMC as ‘markers’, makes sense and should be maintained, even after their identification by molecular cytogenetics.

References


 

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

References


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 their way of formation may be related to Howel Joly Body formation {164}

sSMC might be helpful as gene vectors in future {171}

 

References



 

What do sSMC?

 

  • In 74% of the cases a de novo sSMC has no phenotypic effects! {156}
  • In 1974 it was postulated "that a bisatellited chromosome by association with acrocentric chromosomes may interfere with mitosis at a critical stage of fetal development". {22}
  • Of prenatally ascertained cases with sSMC the following percentage shows abnormal phenotypes:
    18% of 33 cases {13} 30% of 27 cases {42}; 13% of 123 cases {43}.
  • The overall risk for abnormal phenotype is 10.9% for cases with satellited sSMC and 14.7% for cases with non-satellited sSMC {43}.
  • The risk of an abnormal phenotype associated with a de novo sSMC (excluding those derived from chromosome 15) is 7% (if sSMC is from 13, 14, 21 or 22) and 28% (for non-acrocentric chromosomes) {44}.
  • 44% of prenatally ascertained cases with sSMC are familial cases {42} - first report on a 3 generation sSMC without clinical effect described in {71}.
  • "The phenotypes associated with the presence of a marker vary from normal to severely abnormal." {66}
  • It is discussed that sSMC may lead to reduced fertility in males without additional clinical symptoms in connection with the sSMC {57; 65; 69; 90}
  • Of 123 cases with sSMC detected prenatally between 1970 and 1989 in USA 37 were electively terminated, while only 4 of the remaining 86 pregnancies ended with a still birth or spontaneous abortion. 9 additional cases of the 86 cases were born with abnormalities (= 10.5%) {43}.
  • In {160} in 1/2 prenatally detected sSMC the MOM of ßC-hCG:Cr was reduced to 0.31 and in both cases the MOM of free ß-hCG:Cr was enhanced to ~1.5.
  • In one male with normal sperm (normozoospermia) sSMC present in 26% of sperm and 42% of fertilized embryos {168}
  • sSMC have a yet not in detail understood influence on spermatogenesis {179; 180}

References



 

When was the first sSMC described?

 

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}.

References



 

Euchromatin present on and sSMC

 

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 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}
  • micro dissection 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})

 

References



 

Mosaicism in sSMC

 

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]

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

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.

 

References




sSMC and uniparental disomy (UPD)

 

For more details on UPD please see here.

 

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}

 

References



 

Synonyms for sSMC

 

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:

 

  • sSMC = small supernumerary marker chromosome
  • s-SMC = small supernumerary marker chromosome {167}
  • SMC = supernumerary marker chromosome (e.g. {3})
  • AC / ACH = accessory chromosome {58; 73}
  • SAC = small accessory chromosome {74}
  • ESAC = extra structurally abnormal chromosome {14}
  • extra marker chromosome {7}
  • additional marker chromosome {2}
  • supernumerary micro chromosome {9}
  • accessory marker chromosome {10}
  • extra micro chromosome (e.g. {11})
  • additional chromosome fragments {32}
  • minute (centric) fragment {33}
  • bisatellited marker chromosomes {102}
  • metacentric chromosome fragment {103}
  • SRC = supernumerary ring chromosome (e.g. {16})
  • SBAC = small bisatellited additional chromosomes {93}
  • NMC = neocentric marker chromosome {150}
  • SMRC = supernumerary minute ring chromosome {161}
  • MC = marker chromosome {166}
  • CaNC = cancer associated neochromosomes {170} - exceptionally sSMC can be acquired in neoplasia

References



 

Frequency of sSMC

- in newborn
- in prenatal cases
- in mentally retarded
- in subfertile people
- if sSMC is de novo
- if sSMC is acrocentric derived
- of one single UK facility
- if ring chromosome shaped
- according to their chromosomal origin

References


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

References


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.

- 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.

References


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 32930 patients karyotyped in the Belgium center for Human Genetics between 1966 and 1981) {48}

 

References


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

References


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 hreflects 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}

References


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}

References


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

References


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}.

References