Small supernumerary marker chromosome
A small supernumerary marker chromosome 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. 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 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 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 . G banding analyses of sSMCs are commonly used to identify the chromosomes from which they were derived, the arms of these chromosomes they contain, and the parts of the chromosome 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 a ring or centric minute shape, 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.
sSMCs' genes are clearly part of a cells 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. 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, 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. Among sSMC-carrying individuals, ~70% acquired the sSMC as a result of a mutation occurring during formation of their parent's sperm, egg, or zygote, while 30% inherit it directly from a parent carrying the intact sSMC. 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; 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. The sSMC-associated abnormalities include: mild to serious syndromes recognized congenitally 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; 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.
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 such as benign, premalignant, and malignant neoplasms which may be diagnosed at any age.sSMC-associated syndromes
Cat eye syndrome
The Cat eye syndrome, 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 anomalies, male genital anomalies, skeletal defects, borderline to moderately severe intellectual disability, and cat-like downward-slanted openings between the upper and lower eyelids or, less commonly, trisomy of the entire p arm of chromosome 22 plus a small part of this chromosome's q arm. 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. 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, partial tetrasomy 15q, or inverted duplication 15, is a moderate to severe congenital disorder that includes early-life weakness and hypotonia of the central an inverted duplication of the Prader–Willi Syndrome/Angelman Syndrome critical region located between bands 11 and 13 on the q arm of chromosome 15 an area on the q arm of chromosome 15 around band 11 outside of the PWS/ASCR ). Individuals with 15q11-q13 and 15q11-containing sSMC's have sometimes been diagnosed as having the isodicentric (15) syndrome or inv dup syndrome, respectively. Currently, the two syndromes are regarded as types of marker chromosome 15 syndromes that appear to have somewhat different clinical manifestations. 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. The chromosome 15q11-q13 duplication syndrome 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 syndrome and inv dup syndrome are different disorders.Tetrasomy 15qter syndrome
Tetrasomy 15qter syndrome is an extremely rare congenital syndrome which is associated with mental retardation, overgrowth of the body or body part, skull bossing, short palpebral fissures, long philtrum, low-set ears, high-arched palate, retrognathia, joint contractions, arachnodactyly, and/or, less commonly, kidney, genitourinary and various vascular and cardiac anomalies. The syndrome is caused by an sSMC bearing two copies 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 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. 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 tetrasomy 15qter do not have a normal centromere; rather, they have a neocentromere, i.e. a new, novel centromere that forms at a place on the chromosome that is usually not the site where the centromere of the copied chromosome is located. Neocentromeric sSMCs of any type are associated with adverse outcomes in 90% of cases. The exact genetic material in this sSMC that contributes to the development of the cited birth defects has not been determined.Emanuel syndrome
Emanuel syndrome, also known as supernumerary dert syndrome, is characterized by multiple birth defects including craniofacial dysmorphic features, delayed development, intellectual disability, ear anomalies, cleft or high-arched palate, micrognathia, microcephaly, kidney abnormalities, heart defects, and, in males, genital abnormalities. 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, or der22 t, 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. 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 or dert; the afflicted individuals' karyotypes are 47,XX,+dert for females and 47,XY,+dert for males. The sSMC in ES forms as a result of a nondisjunction, 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 dert that produces the defects in ES has not been established.Der(22)t(8;22)(q24.1;q11.1) syndrome
Dert syndrome, also termed the supernumerary dert 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 ; clinodactyly ; and ectopic testis or cryptorchidism. 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 Dert syndrome because they acquired a sSMC that has alteration 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 tchromosomes 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.Tetrasomy 9p
Tetrasomy 9p ''' 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. 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. The genetic material in tetrasomy 9 and trisomy 9p that causes the birth defects is not known. Findings that a) 7 adult cases of tetrasomy 9p were essentially normal and b) many of the genetically detailed cases of tetrasomy 9p have other chromosome abnormalities suggest that the role of the cited sSMCs in tetrasomy 9p requires further study.Isochromosome i (5p)
Isochromosome i 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, shortened survival in the uterus or after birth, psychomotor retardation, facial disfigurements, and/or feeding and/or breathing difficulties. Most cases of isochromosome i 5p are diagnosed in individuals aged 0 to 5 years or, in a few cases, in the uterus. 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. There are large variations in the types of defects shown in individuals with isochromosome i sSMC due, at least in part, to genetic mosaicism, i.e. differences in the tissue and organ distribution of this sSMC.Isochromosome 18p syndrome
Isochromosome 18p syndrome, also termed tetrasomy 18p, is a birth disorder associated with microcephaly, small kidneys, cryptorchidism, micropenis, hypospadias, strabismus, feeding difficulties, neonatal jaundice, kyphosis, scoliosis, recurrent otitis media, hearing loss, constipation, feeding problems, dysmorphic features, and/or moderately severe mental retardation. 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. The specific genetic material on isochromosome 18p sSMC contributing to the development of the syndrome has generally not been assigned. 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.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.