Small supernumerary marker chromosome

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Small supernumerary marker chromosome (sSMC)
Other namesSmall supernumerary chromosome
MarkerChromosomeG-Banding-BMC-Cancer-2006-6-Fig2a.jpg
Representative karyotype from primary passage LX tumor cell 2. Karyotypic deviation: 57XX, +2, i(6)(p10), +7, +7, +8, +9, der(9)t(9 ;12)(p13 ;q11)ins(9;?)(p13;?), +11, +11, +12, +14, +15, +16, −17, del(17)(p11.2) , +21, −22, + mar .
Specialty Medical genetics, pediatrics, oncology, gynecology, urology
Complications Development of birth defects, infertility, neoplasms
Durationlifetime
CausesAbnormal de novo formation in a parent's gametes; direct inheritance from a parent carrying an intact sSMC
Prevention Genetic counseling of carriers

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. [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]

Contents

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. [6] 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. [5] G banding analyses of sSMCs are commonly used to identify the chromosomes from which they were derived, the arms of these chromosomes ("p" for short arm, "q" for long arm) they contain, and the parts of these chromosomes' arms they have as defined by their G band contents. A sSMC containing part of chromosome 15's q arm between G bands 11.2 and 13.1 is described as 15q11.2–q13.1. sSMC's occur in ring or centric minute (linear with a central centromere) shapes, may contain inverted repeats of its genetic material, and may be an isochromosome. Isochromosomes have either two duplicate p or two duplicate q arms rather than the one p and one q arm of normal chromosomes. Thus, cells carrying a sSMC consisting of an isochromosome fragment have 2 extra copies of the genetic material in the sSMC and are termed tetrasomic. Cells carrying sSMCs that contain a non-duplicated fragment of a chromosome have one extra copy of the genetic material and are termed trisomic. [5]

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. [5] Among sSMC-carrying individuals, ~70% acquired the sSMC as a result of a mutation(s) occurring during formation of their parent's sperm, egg, or zygoete while 30% inherited it directly from a parent carrying the intact sSMC (20% from a mother, 10% from a father). Rare cases of sSMCs' associated with neoplasms develop in individuals as a result of acquired mutations in their genome. Some 70% of individuals with a sSMC have no abnormalities and are unaware of it or learn of it by chance; [7] the remaining ~30% acquire abnormalities during prenatal development that may be manifest in utero, at birth, or later in life. About 74% of acquired and >98% of inherited parentally transmitted sSMC-carrying individuals are developmentally normal. [9] The sSMC-associated abnormalities include: mild to serious syndromes recognized congenitally (i.e. at birth) or in the fetus; [5] infertility which is commonly detected in or near adulthood; and benign or malignant tumors that develop at virtually any age. [10] [11] 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 individuals' genomes; [12] 2) variable changes in the genetic material of sSMCs that develop over time; [8] and 3) 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 birth defects diagnosed at an early age, at birth or in a developing fetus; sSMC-associated infertility which is usually diagnosed in adults; and sSMC-related 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 Cat eye syndrome (CES), also termed the Schmid–Fraccaro syndrome, is a severe disorder in which individuals have multiple birth defects such as congenital heart abnormalities, renal malformations, craniofacial anormalies, male genital anomalies, skeleton defects, borderline to moderately severe mental retardation, and cat-like downward-slanted openings between the upper and lower eyelids. CES is commonly associated with a tetrasomy (i.e. four gene copies, one from each normal chromosome, two from the sSMC) or, less commonly, trisomy (three gene copies, one from each normal chromosome and one from the sSMC) of the entire p arm of chromosome 22 plus a small part (i.e. G bands 1 through 11) of this chromosome's q arm. [5] A chromosomal rearrangement mutation between the paired chromosomes 22 occurring during the miosis cell divisions that produce a parent's sperm or egg forms a CES-associated sSMCs that is passed to the parent's offspring. [13] 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. [14] 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. [5] [15] 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. [16]

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, [5] stomach/intestinal disorders, [17] and/or brain abnormalities. [18] The syndrome is associated with a sSMC that contains either: a) an inverted duplication of the Prader–Willi Syndrome/Angelman Syndrome critical region (PWS/ASCR) located between bands 11 and 13 on the q arm of chromosome 15 (notated as 15q,q11,q13); or b) an area on the p arm of chromosome 15 around band 11 (notated as 15q11) outside of the PWS/ASCR (the cytogenic description of this sSMC is dic (15)(q11)). Individuals with 15q,q11,q13 and 15q11 sSMC's have sometimes been diagnosed as having the isodicentric (15) syndrome or inv dup (15) syndrome, respectively. Currently, the two syndromes are regarded as types of marker chromosome 15 syndromes that appear to have somewhat different clinical manifestations. [5] Certain duplicated genes in the PWS/ACR viz., NDN, 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, [5] skull bossing, short palpebral fissures, long philtrum, low-set ears, high-arched palate, retrognathia (i.e., abnormal posterior positioning of the maxilla or mandible), joint contractions, arachnodactyly, and/or, less commonly, kidney, genitourinary [20] and various vascular and cardiac anomalies. [21] 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. [5] Centromeres are specialized DNA sequences of a chromosome that are required to link each sister chromatid of paired chromosomes and thereby to distribute each member of the paired chromosome to different daughter cells during mitosis and meiosis 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

Emanuel syndrome (ES), also known as supernumerary der(22)t(11;22) syndrome, is characterized by multiple birth defects including craniofacial dysmorphic features, delayed development, mental retardation, [5] ear anomalies, cleft or high-arched palate, micrognathia (i.e. undersized jaw), microcephaly (i.e. shorter-than-normal head), kidney abnormalities, heart defects, and, in males, genital abnormalities. [22] 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. [5] The afflicted children of these parents have an ES-producing sSMC containing only part of their parents derivative chromosome. This sSMC is termed derivative 22, der(22) or der(22)t(11;22); the afflicted individuals' karyotypes (i.e. chromosome tallies) are 47,XX,+der(22)t(11;22) for females and 47,XY,+der(22)t(11;22) for males. The sSMC in ES forms as a result of a nondisjunction, [23] 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. [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; 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). [25] 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. [25]

Tetrasomy 9p

Tetrasomy 9p (also termed 9p isochromosome [5] ) is associated with a wide range of birth defects including intrauterine growth retardation; facial dysmorphism; cleft lip and/or palate; malformations of the limbs and skeleton; and/or abnormalities of the central nervous system, heart, and/or 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 [28] [29] ) 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, [29] psychomotor retardation, facial disfigurements, [28] and/or feeding and/or breathing difficulties. [29] Most cases of isochomosome i 5p are diagnosed in individuals aged 0 to 5 years or, in a few cases, in the uterus. [29] A 2018 review of 15 postnatal cases that had genetic analyses found 4 were associated with amplifications due to mutations in chromosome 5's p arm and 8 were associated with sSMCs consisting of two partial copies of this arm. All 12 individuals had 2 extra copies of large areas in the p arm. However, the exact genetic material on the p arm contributing to the disorder were not established. Individuals with only one extra partial copy of th 5p arm, i.e. who were trisomic, have similar but perhaps less severe defects than those with tetrasomy i (5p). [30] 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. [29]

Isochromosome 18p syndrome

Isochromosome 18p syndrome, [5] also termed tetrasomy 18p, is a birth disorder associated with microcephaly (shorter than normal head), small kidneys, cryptorchidism, micropenis, hypospadias (i.e. the penis's 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, identical female twins, i.e. twins with essentially identical copies of their parent's chromosomes, were studied because one twin clearly had the isochromosome 18p syndrome while the other appeared completely normal. Genetic analysis found evidence for the presence of isochromosome 18p's sSMC in almost all or all the cells isolated from the inner cheek, hair follicles, and skin fibroblasts of the afflicted twin while the normal twin had ≤5% of the cells in these samples positive for this sSMC. Neither parent showed evidence of having the sSMC. Thus, the normal twin appeared to have an extreme form of 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

Turner syndrome is a condition in which females typically have only one X chromosome and either no Y or only part of a Y chromosome. These individuals exhibit a wide range of relatively mild to moderately severe birth defects including in all cases short stature; in most cases ovarian failure and infertility; and in less common cases bone anomalies, lymphoedema, deafness, and/or cardiovascular, thyroid and gastrointestinal disorders. [34] [35] 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. [36] 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. [5]

sSMC-associated infertility

Infertility as used here occurs in individuals who have no other overt birth defects. [35] As such, it is diagnosed three times more often in individuals possessing sSMCs and occurs in 0.125% of all infertility cases. [37] 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. [3] A review published in 2015 reported that the sSMC's in infertile men contain parts of any chromosome except chromosomes 10, 19, and X, with chromosomes 15, 14, 22, and 13/21 (i.e. a complex sSMC consisting of parts of chromosomes 13 and 21) being the most common. [38] 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]). [3] Infertility associated with a sSMC in women is ~7.5-fold less common than in men [37] but, like men, their sSMC's consist of almost any chromosome but particularly chromosomes 15, 14, 22, and 13/21. Clinically, women with sSMC-associated infertility have a history of amenorrhea and/or primary ovarian insufficiency, i.e. premature menopause or symptoms related to premenopausal events such as partial or total losses of estrogens, progesterone, androstenedione, activin, and/or 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

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. [11] [40] 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. [40] [41] 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 [42] and 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 osteosarcomas (LGO), including low grade central and parosteal osteosarcomas, are far less malignant than most other types of osteosarcoma bone tumors. [46] 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. [47] 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 [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 SRY gene located on the p arm of the Y chromosome at band 11.2 (notated as Yp11.2). This gene encodes the testis-determining factor protein (also known as sex-determining region Y protein). Turner syndrome individuals with this SRY gene-containing sSMC have an increased incidence of developing gonadal tissue neoplasms such as gonadoblastomas and in situ seminomas (also termed dysgerminoma to indicate that this tumor has the pathology of the testicular tumor, seminoma, but develops in ovaries [49] ). Otherwise, these individual have typical features of the Turner syndrome except for a minority who also have hirsutism and/or clitoral enlargement. [50] Surgical removal of 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 cancer-related mutations in the bearer's genome. [5] sSMC i(5)(p10) is the single most common recurrent structural chromosomal abnormality in transitional cell carcinomas of the 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

Related Research Articles

<span class="mw-page-title-main">Turner syndrome</span> Chromosomal disorder in which a female is partially or completely missing an X chromosome

Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic disorder caused by a sex chromosome monosomy, compared to the two sex chromosomes in most people, it only affects women. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet are seen at birth. Typically, those affected do not develop menstrual periods or breasts without hormone treatment and are unable to have children without reproductive technology. Heart defects, diabetes, and low thyroid hormone occur in the disorder more frequently than average. Most people with Turner syndrome have normal intelligence; however, many have problems with spatial visualization that may be needed in order to learn mathematics. Vision and hearing problems also occur more often than average.

<span class="mw-page-title-main">Aneuploidy</span> Presence of an abnormal number of chromosomes in a cell

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any number of complete chromosome sets is called a euploid cell.

<span class="mw-page-title-main">Liposarcoma</span> Medical condition

Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the precursor lipoblasts of the adipocytes in adipose tissues. Adipose tissues are distributed throughout the body, including such sites as the deep and more superficial layers of subcutaneous tissues as well as in less surgically accessible sites like the retroperitoneum and visceral fat inside the abdominal cavity.

<span class="mw-page-title-main">Azoospermia</span> Medical condition of a man whose semen contains no sperm

Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.

<span class="mw-page-title-main">Isochromosome</span>

An isochromosome is an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other. The chromosome consists of two copies of either the long (q) arm or the short (p) arm because isochromosome formation is equivalent to a simultaneous duplication and deletion of genetic material. Consequently, there is partial trisomy of the genes present in the isochromosome and partial monosomy of the genes in the lost arm.

<span class="mw-page-title-main">Polysomy</span> Abnormal multiples of one or more chromosomes

Polysomy is a condition found in many species, including fungi, plants, insects, and mammals, in which an organism has at least one more chromosome than normal, i.e., there may be three or more copies of the chromosome rather than the expected two copies. Most eukaryotic species are diploid, meaning they have two sets of chromosomes, whereas prokaryotes are haploid, containing a single chromosome in each cell. Aneuploids possess chromosome numbers that are not exact multiples of the haploid number and polysomy is a type of aneuploidy. A karyotype is the set of chromosomes in an organism and the suffix -somy is used to name aneuploid karyotypes. This is not to be confused with the suffix -ploidy, referring to the number of complete sets of chromosomes.

<span class="mw-page-title-main">XXYY syndrome</span> Extra X and Y chromosome in males

XXYY syndrome is a sex chromosome anomaly in which males have 2 extra chromosomes, one X and one Y chromosome. Human cells usually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). The appearance of at least one Y chromosome with a properly functioning SRY gene makes a male. Therefore, humans with XXYY are genotypically male. Males with XXYY syndrome have 48 chromosomes instead of the typical 46. This is why XXYY syndrome is sometimes written as 48, XXYY syndrome or 48, XXYY. It affects an estimated one in every 18,000–40,000 male births.

The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short arm of chromosome 12. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12's are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related birth defects and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart.

A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.

<span class="mw-page-title-main">Isodicentric 15</span> Condition caused by two joined and mirrored duplications of part of chromosome 15

Isodicentric 15, also called marker chromosome 15 syndrome, idic(15), partial tetrasomy 15q, or inverted duplication 15, is a chromosome abnormality in which a child is born with extra genetic material from chromosome 15. People with idic(15) are typically born with 47 chromosomes in their body cells, instead of the normal 46. The extra chromosome, which is classified as a small supernumerary marker chromosome, is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Individuals with idic(15) have a total of four copies of this chromosome 15 region instead of the usual two copies. The term isodicentric refers to a duplication and inversion of a centromere-containing chromosomal segment.

<span class="mw-page-title-main">Transitional cell carcinoma</span> Medical condition

Transitional cell carcinoma, also called urothelial carcinoma, is a type of cancer that typically occurs in the urinary system. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus. Symptoms of urothelial carcinoma in the bladder include hematuria. Diagnosis includes urine analysis and imaging of the urinary tract (cystoscopy). Transitional cell carcinomas arise from the transitional epithelium, a tissue lining the inner surface of these hollow organs. When the term "urothelial" is used, it specifically refers to a carcinoma of the urothelium, meaning a transitional cell carcinomas of the urinary system.

Emanuel syndrome, also known as derivative 22 syndrome, or der(22) syndrome, is a rare disorder associated with multiple congenital anomalies, including profound intellectual disability, preauricular skin tags or pits, and conotruncal heart defects. It can occur in offspring of carriers of the constitutional chromosomal translocation t(11;22)(q23;q11), owing to a 3:1 meiotic malsegregation event resulting in partial trisomy of chromosomes 11 and 22. An unbalanced translocation between chromosomes 11 and 22 is described as Emanuel syndrome. It was first described in 1980 by American medical researchers Beverly S. Emanuel and Elaine H. Zackai, and a consortium of European scientists the same year.

A marker chromosome (mar) is a small fragment of a chromosome which generally cannot be identified without specialized genomic analysis due to the size of the fragment. The significance of a marker is variable as it depends on what material is contained within the marker. The large majority of these marker chromosomes are smaller than one of the smaller human chromosomes, chromosome 20, and by definition are termed small supernumerary marker chromosomes.

<span class="mw-page-title-main">Tetrasomy 18p</span> Presence of four copies of the short arm of chromosome 18

Tetrasomy 18p is a genetic condition that is caused by the presence of an isochromosome composed of two copies of the short arm of chromosome 18 in addition to the two normal copies of the chromosome. It is characterized by multiple medical and developmental concerns.

<span class="mw-page-title-main">Cat eye syndrome</span> Genetic partial duplication of chromosome 22

Cat-eye syndrome (CES) or Schmid–Fraccaro syndrome is a rare condition caused by an abnormal extra chromosome, i.e. a small supernumerary marker chromosome. This chromosome consists of the entire short arm and a small section of the long arm of chromosome 22. In consequence, individuals with the cat-eye syndrome have three (trisomic) or four (tetrasomic) copies of the genetic material contained in the abnormal chromosome instead of the normal two copies. The prognosis for patients with CES varies depending on the severity of the condition and their associated signs and symptoms, especially when heart or kidney abnormalities are seen.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

<span class="mw-page-title-main">Tetrasomy 9p</span> Presence of four copies of the short arm of chromosome 9

Tetrasomy 9p is a rare chromosomal disorder characterized by the presence of two extra copies of the short arm of chromosome 9, in addition to the usual two. Symptoms of tetrasomy 9p vary widely among affected individuals but typically include varying degrees of delayed growth, abnormal facial features and intellectual disability. Symptoms of the disorder are comparable to those of trisomy 9p.

About 10–15% of human couples are infertile, unable to conceive. In approximately in half of these cases, the underlying cause is related to the male. The underlying causative factors in the male infertility can be attributed to environmental toxins, systemic disorders such as, hypothalamic–pituitary disease, testicular cancers and germ-cell aplasia. Genetic factors including aneuploidies and single-gene mutations are also contributed to the male infertility. Patients with nonobstructive azoospermia or oligozoospermia show microdeletions in the long arm of the Y chromosome and/or chromosomal abnormalities, each with the respective frequency of 9.7% and 13%. A large percentage of human male infertility is estimated to be caused by mutations in genes involved in primary or secondary spermatogenesis and sperm quality and function. Single-gene defects are the focus of most research carried out in this field.

<span class="mw-page-title-main">Tetrasomy X</span> Chromosomal disorder with 4 X chromosomes

Tetrasomy X, also known as 48,XXXX, is a chromosomal disorder in which a female has four, rather than two, copies of the X chromosome. It is associated with intellectual disability of varying severity, characteristic "coarse" facial features, heart defects, and skeletal anomalies such as increased height, clinodactyly, and radioulnar synostosis. Tetrasomy X is a rare condition, with few medically recognized cases; it is estimated to occur in approximately 1 in 50,000 females.

<span class="mw-page-title-main">Pentasomy X</span> Chromosomal disorder

Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, heart defects, skeletal anomalies, and pubertal and reproductive abnormalities. The condition is exceptionally rare, with an estimated prevalence between 1 in 85,000 and 1 in 250,000.

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