Small supernumerary marker chromosome

A small supernumerary marker chromosome (sSMC) is an abnormal extra chromosome. It contains copies of parts of one or more normal chromosomes and like normal chromosomes is located in the cell's nucleus, is replicated and distributed into each daughter cell during cell division, and typically has genes which may be expressed. However, it may also be active in causing birth defects and neoplasms (e.g. tumors and cancers). The sSMC's small size makes it virtually undetectable using classical cytogenetic methods: the far larger DNA and gene content of the cell's normal chromosomes obscures those of the sSMC. Newer molecular techniques such as fluorescence in situ hybridization, next generation sequencing, comparative genomic hybridization, and highly specialized cytogenetic G banding analyses 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.

Human cells typically have 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Each member of the paired autosomal chromosomes is identified as chromosome 1 up to 22; the pair of sex chromosomes are identified as the X and Y chromosomes with women's cells bearing two X chromosomes and men's cells bearing one X and one (male sex-determining) Y chromosome. sSMC are, by definition, smaller in size than one of the smaller human chromosomes, chromosome 20. They originate as copies of relatively small parts of one or more of the 46 chromosomes. Not all chromosomes are equally represented in sSMCs: ~65% of all sSMCs are copies of parts of chromosome 15 while only 7% are copies of parts of one of the five acrocentric chromosomes viz., chromosomes 13, 14, 15, 21, and 22 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 form an sSMC de novo during the meiosis divisions that form the sperm or egg cell, and subsequently the zygote (i.e. fertilized egg), which then develops into a fetus. Less commonly, however, parents may carry the sSMC and pass it to their descendants through their sperm or egg. In either case, the sSMCs may acquire further changes in their genetic material at any time during development of the zygote or thereafter.

World-wide, small supernumerary marker chromosomes occur in ~4.2 per 10,000 individuals. The sSMC-associated abnormalities include: mild to serious syndromes recognized congenitally (i.e. at birth) or in the fetus; There is a wide range of characteristics and traits among individuals with the same or similar sSMC. This is due to at least three mechanisms: 1) differences in the genomic contents of the sSMCs and/or individual genomes; 2) variable changes in the genetic material of sSMCs that develop over time; Rarely, CES results from a balanced translocation between a parent's paired chromosome 22. A balanced translocation is an even exchange between two chromosomes that results in no change in genetic information and generally has no detrimental effects on its carriers. However, a parent with a balanced translocation in chromosomes 22 has an increased risk of having a child with CES; this is due to a chromosomal rearrangement mutation between the balanced chromosomes 22 that forms a sSMC-associated sSMC in the parent's sperm or egg and is passed to the parent's offspring. Finally, in extremely rare cases a parent may carry a CES-associated sSMC in only some of their cells due to mosaicism, have little of no CES defects, and directly transmit this sSMC through their sperm or eggs to their offspring. A CES-associated sSMC may be small, large, or ring-shaped and typically includes 2 Mb, i.e. 2 million DNA base pairs, termed the CES critical region, located on its q arm at bands 11.1 through ll.23. This area contains the CECR1, SLC22A18, and ATP6V1E1 genes which are strong candidate genes for causing or promoting at least some of the birth defects in CES.

Marker chromosome 15 syndrome

Marker chromosome 15 syndrome, also called Isodicentric 15, idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15), is a moderate to severe congenital disorder that includes early-life weakness and hypotonia of the central (but not limb) muscles, delays in normal development, intellectual disability, autistic behavior, epilepsy, and/or brain abnormalities. 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. 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

Tetrasomy 15qter syndrome is an extremely rare congenital syndrome which is associated with intellectual disability, overgrowth of the body or body part, and various vascular and cardiac anomalies. The syndrome is caused by an sSMC bearing two copies (that are inverted duplications) of the genetic material on the q arm of chromosome 15 beginning at various sites between bands 23 and 26 and running to this arms terminus; this area is notated as (15) q24–qter. Individuals with this syndrome therefore have 4 copies of the genetic material that is in the sSMC, i.e. 2 from each normal chromosome and 2 from the sSMC. ES is associated with a sSMC containing genetic material from a derivative chromosome carried by one parent. A derivative chromosome contains a balanced translocation, i.e. an even exchange between two chromosomes that results in no increase or decrease in genetic information and generally has no detrimental effects on its carriers. This derivative chromosome contains an exchange, termed t(11;22), or der22 (22) t (11;22), between the q arm of chromosome 22 around band 11.2 and the q arm of chromosome 11 around band 21. In ~10% of cases, carriers of this chromosome have a child with ES, with male and female carriers having 0.7% and 3.4%, respectively, chances of parenting such a child. i.e. failure, of the parent's derivative chromosome to separate from its homolog, i.e. paired, chromosome properly during the 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.

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 intellectual disability; dysmorphic features in the face and head areas; prominent, low-set, underdeveloped ear canals, and/or preauricular pits (small holes or cysts in front and above the ear canal); clinodactyly (abnormal curvature of one or more fingers and/or toes); and ectopic testis (testes in unusual locations) or cryptorchidism (undescended testes). This syndrome is associated with a sSMC derived from an abnormal chromosome carried by a parent. This chromosome contains a 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. The genetic material in tetrasomy 9 and b) many of the genetically detailed cases of tetrasomy 9p have other chromosome abnormalities) is a congenital disorder associated with a wide range of birth defects the most common of which are: developmental delay, hypotonia, short stature, seizures, congenital heart defects, ventriculomegaly (enlargement of the brain's lateral ventricles), shortened survival in the uterus or after birth, There are large variations in the types of defects shown in individuals with isochromosome i (5P) sSMC due, at least in part, to genetic mosaicism, i.e. differences in the tissue and organ distribution of this sSMC. and/or moderately severe intellectual disability. The specific genetic material on isochromosome 18p sSMC contributing to the development of the syndrome has generally not been assigned. PKS is commonly caused by an sSMC that is an isochromosome consisting of two p arms of chromosome 12 A small percentage of Turner syndrome individuals have sSMCs that contain parts of the genetic material from an X or, much less frequently, Y chromosome. These sSMCs may or may not contain an XIST gene. In normal females, the XIST gene occurs on the X chromosome inherited from her mother but not on the X chromosome inherited from her father. The gene is not present on Y chromosomes and in normal females resides on and functions to inactivate many of the genes located on its own maternal but not the father's X chromosome. Turner syndrome females with an sSMC consisting of a partial X chromosome that does not contain the XIST gene express at least some of this sSMC's genetic material and therefore contain excesses of this material. In consequence, they have a more serious form of the Turner syndrome that ranges form moderately severe to extremely severe. The extremely severe cases have anencephaly (absence of a major portion of the brain, skull, and scalp), agenesis of the corpus callosum (lack of the thick tract of nerve fibers that connect the left and right 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. Infertile men cannot impregnate, have abnormally low rates of impregnation, and/or impregnate their partner but their impregnations have abnormally high rates of spontaneous abortion. Clinically, these men have either azoospermia (i.e. absence of sperm), oligozoospermia (i.e. abnormally low sperm counts), or aoligoasthenoteratozoospermia (i.e. all three of the following, oligozoospermia, teratozoospermia [i.e. presence of sperm with abnormal shapes], and asthenozoospermia [i.e. sperm with reduced motility]). The specific genetic material producing infertility in these sSMCs has, in general, not been clearly defined.

sSMC-associated neoplasms

Atypical lipomatous tumors

Atypical lipomatous tumors (ALTs) are a type of well-differentiated liposarcoma. The term ALT is often applied to tumors located in surgically accessible locations such as the skin, oral cavity, or eye socket whereas the term well-differentiated liposarcomas is applied to tumors in less surgically accessible, deep, and centrally located, soft tissues such as the retroperitoneum. Here, the two terms are used interchangeably. Unlike less well-differentiated liposarcomas which are malignant, ALTs, while sometimes locally invasive and recurring after surgical removal, do not metastasize and rarely progress to less differentiated and potentially metastasizing forms. They are therefore commonly regarded as benign or premalignant tumors. The neoplastic cells in ALT contain one or more ring-shaped sSMCs or one giant marker chromosome (i.e. a chromosome enlarged by having a duplication of parts of its own or one or more other chromosomes) that contain extra copies of chromosome 12's q arm at bands 13 through 15. This stretch of chromosome 12 includes the MDM2 proto-oncogene (a potentially tumor-causing gene) located at band 15 and CDK4 (a gene associated with the development of various tumors) located at band 14.1. 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. 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 osteosarcomas (LGO), including low grade central and parosteal osteosarcomas, are far less malignant than most other types of osteosarcoma bone tumors. The tumor cells in LGO contain either supernumerary ring sSMCs or giant rod-shaped marker chromosomes (also termed giant rod chromosomes or RGMs). RGMs are supernumerary (i.e. extra) chromosomes that are larger than chromosome 20 and therefore here regarded too large to be classified as sSMCs. The sSMCs and RGMs in LGO contain a part of the q arm of chromosome 12 that includes its band 13 through band 15 (notated as 12q13–15). Several genes amplified in the neoplastic cells of various other types of cancer are in and thereby may be amplified in the LGO-associated sSMC and giant rod chromosomes. These genes include MDM2, CDK4, FRS2, HMGA2, YEATS4 (YEATS4 is YEATS domain containing 4), 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.). Otherwise, these individual have typical features of the Turner syndrome except for a minority who also have hirsutism and/or clitoral enlargement. Surgical removal of the gonads has been recommended to remove the threat of developing these sSMC-associated neoplasms. Turner syndrome individuals with sSMCs that lacks the SRY gene are not at an increased risk of developing these cancers. sSMC i(5)(p10), often in two or more copies, is also found in the malignant cervical cancer cells of individuals 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. sSMC i (5)(p10) is also detected in rare cases of ovarian cancer and very rare cases of breast cancers.