Small supernumerary marker chromosome

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Small supernumerary marker chromosome (sSMC)
Other namesSmall supernumerary chromosome
neoplasms
Durationlifetime
CausesAbnormal de novo formation in a parent's gametes; direct inheritance from a parent carrying an intact sSMC
PreventionGenetic counseling of carriers

A small supernumerary marker chromosome (sSMC) is an abnormal extra

cytogenetic methods: the far larger DNA and gene content of the cell's normal chromosomes obscures those of the sSMC.[1] Newer molecular techniques such as fluorescence in situ hybridization,[2] next generation sequencing, comparative genomic hybridization,[3] and highly specialized cytogenetic G banding analyses[4] are required to study it. Using these methods, the DNA sequences and genes in sSMCs are identified and help define as well as explain any effect(s) it may have on individuals.[5]

Human

sSMCs' genes are clearly part of a cell's genotype, i.e. gene profile, but may not be activatable and therefore not alter an individual. In many cases, however, the genes in a sSMCs are active, over-expressed, and considered causes of the associated sSMC's disorder.[7] sSMCs may form as a result of one or more of the following chromosomal events: incomplete trisomic rescue, chromothripsis-mediated partial trisomy rescue, U-type strand exchange, and/or rare types of genetic recombination. These events typically from an sSMC de novo during the meiosis divisions that form the sperm or egg cell or subsequently the zygote (i.e. fertilized egg) which develops into a fetus. Less commonly, however, parents may carry the sSMC and pass it to their descendants through their sperms or eggs. In either case, the sSMCs may acquire further changes in their genetic material at any time during development of the zygote or thereafter.[8]

World-wide, small supernumerary marker chromosomes occur in ~4.2 per 10,000 individuals.

genetic mosaicism, i.e. variations in the distribution of the sSMC to different tissues and organs that occur during embryonic development or thereafter.[7]

sSMC-associated disorders

There are numerous sSMC-associated disorders, most of which have been reported to occur in just a few individuals. The following sections detail some sSMC-associated disorders that are found in larger numbers of individuals, are genetically well-characterized, and/or exemplify novel aspects or impacts of particular sSMCs. Overall, these disorders are classified as: sSMC-associated syndromes that cause serious

neoplasms (i.e. abnormal and excessive growth of tissues) such as benign, premalignant, and malignant neoplasms which may be diagnosed at any age.[citation needed
]

sSMC-associated syndromes

Cat eye syndrome

The

candidate genes for causing or promoting at least some of the birth defects in CES.[16]

Marker chromosome 15 syndrome

SNRPN, UBE3A, and GABRB3, are suspected of contributing to one or more of the disorders in this syndrome.[18] The chromosome 15q11-q13 duplication syndrome (also termed Dup15q) is associated with birth defects similar to those of marker chromosome 15 syndrome. It is caused by a duplication of bands q11 through q13 on chromosome 15 which, like the sSMC in most cases of the marker chromosome 15 syndrome, includes PWS/ASCR and the genes just cited.[19]
Further studies are needed to define the roles of the cited genes, if any, in the birth defects associated with the Marker 15 chromosome and/or chromosome 15q11-q13 duplication syndromes. Future studies may also determine that isodicentric (15) syndrome and inv dup (15) syndrome are different disorders.

Tetrasomy 15qter syndrome

Tetrasome 15qter syndrome is an extremely rare congenital syndrome which is associated with mental retardation, overgrowth of the body or body part,

cell divisions. The sSMCs in tetraseome 15qter do not have a normal centromere; rather, they have a neocentromere, i.e. a new centromere that forms at a place on the chromosome that is usually not the site where the centromere of the copied chromosome (in this case chromosome 15) is located.[20] Neocentromeric sSMCs of any type are associated with adverse outcomes in 90% of cases.[5] The exact genetic material in this sSMC that contributes to the development of the cited birth defects has not been determined.[21]

Emanual syndrome

meiotic cell divisions that form their sperms or eggs. The genetic material in sSMC der(22)t(11;22) that produces the defects in ES has not been established.[22][24]

Der(22)t(8;22)(q24.1;q11.1) syndrome

Der(22)t(8;22)(q24.1;q11.1) syndrome, also termed the supernumerary der(22)t(8;22) syndrome, is a syndrome in which individuals are born with normal birth weight and growth but have moderate mental retardation;

balanced translocation between the q arm around band 24.13 of chromosome 8 and the q arm around band 11.1 of chromosome 22. Carriers of it are at risk of having progeny with the Der(22)t(8;22)(q24.1;q11.1) syndrome because they acquired a sSMC that has alteration(s) in the parent's abnormal chromosome. This alteration occurs in the parent's egg or sperm as a result of an nondisjunction of the parent's paired t(8;22)chromosomes during the meiosis cell divisions that form the sperm or egg. The genetic material in this sSMC that causes this syndrome's defects has not been established.[25]

Tetrasomy 9p

genitourinary tract.[7] The sSMC in tetrasomy 9 cases is an isochromosome of one of 3 compositions: a) two p arms of chromosome 9 which are mirror images of each other; b) this chromosome's two p arms plus a small part of its q arm from bands 12 to 13; or c) this chromosomes two p arms plus a part of its q arm from bands 21 to 22. All three of these sSMC variant types contain two copies of the p arm genetic material that they contain and therefore render cells tetrasomeic, i.e. possessing 4 copies, of some of this arm's genetic material.[7] However, there is a trisomy 9p-related congenital disorder which has only 3 copies of this genetic material due an abnormal chromosome 12 containing duplicate copies rather than a single copy of some genetic material. These individuals have trisomy 9p; they have birth defects similar to, but less severe than, those in tetrasomy 9p.[26] The genetic material in tetrasomy 9[5] and trisomy 9p[26] that causes the birth defects is not known. Findings that a) 7 adult cases of tetrasomy 9p were essentially normal[27] and b) many of the genetically detailed cases of tetrasomy 9p have other chromosome abnormalities[26]
suggest that the role of the cited sSMCs in tetrasomy 9p requires further study.

Isochromosome i (5p)

Isochromosome i (5p) (also termed tetrasomy 5p

genetic mosaicism, i.e. differences in the tissue and organ distribution of this sSMC.[29]

Isochromosome 18p syndrome

urethral opening is mis-located), strabismus, feeding difficulties, neonatal jaundice, kyphosis (excessive convex curvature of the spine), scoliosis (sideways curve of the spine), recurrent otitis media, hearing loss, constipation, feeding problems, dysmorphic features,[31] and/or moderately severe mental retardation.[5] The sSMc in this syndrome is composed of two extra copies of the short arm of chromosome 18 developed in most cases during formation of a parent's egg or sperm or in the fertilized zygote although rare inherited cases of the intact sSMC have been reported.[5][32] The specific genetic material on isochromosome 18p sSMC contributing to the development of the syndrome has generally not been assigned.[32] However, a recent report on one individual with the syndrome revealed a sSMC of at least 15 Mb extending from band 11.21 to ll.32 on the p arm of chromosome 18.[31]

Recently,

mosaicism in which the sSMC was present in too few tissue cells to cause the birth defects associated with the isochromosome 15p syndrome. Extreme levels of sSMC mosaicism in this and possibly other sSMC-associated disorders can be well tolerated, not associated with birth defects, and more common than currently considered.[32]

Pallister–Killian syndrome

Pallister–Killian syndrome (PKS) is a congenital disorder that includes an extremely wide range of birth defects. The most common of these are facial dysmorphism, pigmentary skin anomalies, profound intellectual disability, hypotonia, and/or seizures; some of its less common defects include deafness, extra breast nipples, congenital diaphragmatic hernias, and/or focal areas of absent skin.[33] PKS is commonly caused by an sSMC that is an isochromosome consisting of two p arms of chromosome 12[5] but in less common cases four p arms of this chromosome.[33] Recent studies in two individuals with PKS found the sSMC consisted of two small duplications from band 11 to the terminus of the p arm on chromosome 12. This area, termed the PKS critical region, contains three genes, ING4, CHD4, and MFAP5 (also termed the MAGP2 gene), one or more of which is a candidate causer of the syndrome.[33]

Turner syndrome

cerebral hemispheres), and complex heart deformities. Individuals with Turner syndrome that have partial X chromosome containing-sSMCs that have the XIST gene do not express this sSMC's genetic material and do not suffer the cited severer manifestations of the syndrome.[5]

sSMC-associated infertility

inhibin production by the ovaries before age 40.[38] While only a small percentage of the chromosome areas involved in infertility due to sSMC's have been defined, those that have include: (15)q11.1, associated with premature ovarian failure; (13)q11.2, associated with oligoasthenoteratozoospermia;[38] (14)q11.1, associated with infertility; and (22)q11, associated with repeated abortions.[39]
The specific genetic material producing infertility in these sSMCs has, in general, not been clearly defined.

sSMC-associated
neoplasms

Atypical lipomatous tumors

CDK4 (a gene associated with the development of various tumors) located at band 14.1.[43][44] The presence of these two genes is a highly sensitive and specific indicator that a lipomatous tumor is an ALT rather than another type of lipomatous tumor.[44] The sSMCs and giant marker chromosomes involved in ALT may contain sequences from other chromosomes; furthermore, the ring sSMCs frequently break, reseal, transform into a rod-shape, and develop gains and/or losses in their genetic material. These factors may help promote the survival and growth of the sSMC-bearing neoplastic cells in ATMs.[45]
As a result of these complicating factors, the specific genetic material in the sSCMs and giant marker chromosomes responsible for the development of ALTs have not been established.

Osteosarcomas

Low grade

CDK4, FRS2, HMGA2, YEATS4 (YEATS4 is YEATS domain containing 4[48]), and CPM. The MDM2, CDK4, and FRS2 genes are amplified in 67% to 100% of all LGO cases and are suspected of contributing to the development and/or progression of LGOs.[10] However, both the sSMCs and RGMs in LGO commonly contain parts of various other chromosomes, may be multiple, and often undergo changes in there genetic material during cell divisions. Consequently, the specific genetic material responsible for the formation and development of LGO has been difficult to define.[45]

Gonadal tumors in the Tuner syndrome

Most individuals with Turner syndrome have one X and no Y chromosome. However, about 5.5% of Turner syndrome individuals have an sSMC containing part of a Y chromosome. This partial Y chromosome-bearing sSMC may include the

gonads has been recommended to remove the threat of developing these sSMC-associated neoplasms.[50][51][52] Tuner syndrome individuals with sSMCs that lacks the SRY gene are not at an increased risk of developing these cancers.[50]

Isochromosome i (5p)(p10)-associated cancers

A sSMC containing isochromosome i (5p)(p10) (see above section on the isochcromosome 18p syndrome) has been documented to be present in the malignant cells of certain types of cancer. Its presence in these cells is not due to inheritance but rather to

urinary bladder, being present in the malignant cells of most cases of this disease. Transitional cell bladder carcinomas associated with this sSMS are more aggressive and invasive than those not associated with it.[53] sSMC i(5)(p10), often in two or more copies, is also found in the malignant cervical cancer cells of individuals[54] as well as in the oldest and most commonly studied immortalised cell line, HeLa cells. These cells were isolated from the cervix tumor of Henrietta Lacks, a 31-year-old African-American who died of her cancer in 1951.[55] sSMC i (5)(p10) is also detected in rare cases of ovarian cancer and very rare cases of breast cancers.[5] The mechanism(s) by which these sSMCs promote the development and/or progression of these cancer types is unclear.[56]

See also

References

External links