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 (note that the human Y chromosome can sometimes appear acrocentric, but this is usually the result of a translocation from an autosome). 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 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 (linear with a central centromere) 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 (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. 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 zygote, while 30% inherit 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; 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 (i.e. at birth) or in the fetus; infertility which is commonly detected in or near adulthood; and benign or malignant tumors that develop at virtually any age. 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; 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 (i.e. abnormal and excessive growth of tissues) such as benign, premalignant, and malignant neoplasms which may be diagnosed at any age.
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 anomalies, male genital anomalies, skeletal defects, borderline to moderately severe intellectual disability, and cat-like downward-slanted openings between the upper and lower eyelids (palpebral fissures. 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. 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(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, stomach/intestinal disorders, and/or brain abnormalities. 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 15q11-q13); or b) an area on the q 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 15q11-q13 and 15q11-containing 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. 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 (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, 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 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. 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 (in this case chromosome 15) 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