Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification

Small supernumerary marker chromosomes (SMCs) are present in about 0.05% of the human population. In approximately 30% of SMC carriers (excluding the ~60% SMC derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. The clinical outcome of an SMC is difficult to predict as they can have different phenotypic consequences because of (1) differences in euchromatic DNA-content, (2) different degrees of mosaicism, and/or (3) uniparental disomy (UPD) of the chromosomes homologous to the SMC. Here, we present 35 SMCs, which are derived from all human chromosomes, apart from chromosome 6, as demonstrated by the appropriate molecular cytogenetic approaches, such as centromere-specific multicolor fluoresence in situ hybridization (cenM-FISH), multicolor banding (MCB), and subcentromere-specific multicolor FISH (subcenM-FISH). In nine cases without an aberrant phenotype, neither partial proximal trisomies nor UPD could be detected. Abnormal clinical findings, such as psychomotoric retardation and/or craniofacial dysmorphisms, were associated with seven of the cases in which subcentromeric single-copy probes were proven to be present in three copies. Conversely, in eight cases with a normal phenotype, proximal euchromatic material was detected as partial trisomy. UPD was studied in 12 cases and subsequently detected in two of the cases with SMC (partial UPD 4p and maternal UPD 22 in a der(22)-syndrome patient), indicating that SMC carriers have an enhanced risk for UPD. At present, small proximal trisomies of 1p, 1q, 2p, 6p, 6q, 7q, 9p, and 12q seem to lead to clinical manifestations, whereas partial proximal trisomies of 2q, 3p, 3q, 5q, 7p, 8p, 17p, and 18p may not be associated with significant clinical symptoms. With respect to clinical outcome, a classification of SMCs is proposed that considers molecular genetic and molecular cytogenetic characteristics as demonstrated by presently available methods.Electronic database information: accession numbers and URLs for the data in this article are as follows:ENSEMBL-database, National Center for Biotechnology Information (NCBI), Genome Database (GDB), OMIM (Online Mendelian Inheritance in Man) Database,     

Somatic mosaicism in cases with small supernumerary marker chromosomes

Somatic mosaicism is something that is observed in everyday lives of cytogeneticists. Chromosome instability is one of the leading causes of large-scale genome variation analyzable since the correct human chromosome number was established in 1956. Somatic mosaicism is also a well-known fact to be present in cases with small supernumerary marker chromosomes (sSMC), i.e. karyotypes of 47,+mar/46. In this study, the data available in the literature were collected concerning the frequency mosaicism in different subgroups of patients with sSMC. Of 3124 cases with sSMC 1626 (52%) present with somatic mosaicism. Some groups like patients with Emanuel-, cat-eye- or i(18p)- syndrome only tend rarely to develop mosaicism, while in Pallister-Killian syndrome every patient is mosaic. In general, acrocentric and non-acrocentric derived sSMCs are differently susceptible to mosaicism; non-acrocentric derived ones are hereby the less stable ones. Even though, in the overwhelming majority of the cases, somatic mosaicism does not have any detectable clinical effects, there are rare cases with altered clinical outcomes due to mosaicism. This is extremely important for prenatal genetic counseling. Overall, as mosaicism is something to be considered in at least every second sSMC case, array-CGH studies cannot be offered as a screening test to reliably detect this kind of chromosomal aberration, as low level mosaic cases and cryptic mosaics are missed by that.     

Parallel mosaicism of supernumerary chromosomes and sex chromosomes in Echymipera kalabu (Marsupialia)

Echymipera kalabu (Peramelidae: Marsupialia) does not have the full chromosome complement in all its adult somatic tissues. The chromosomes missing are the Y-chromosome in the male and an X-chromosome in the female. The full complement is present in the corneal epithelium and the reproductive tissue. A parallel mosaicism to this exists with respect to small supernumerary chromosomes which are found in certain animals of this species. These supernumeraries must be subject to the same control system as that which is responsible for the elimination of the sex chromosomes.     

Characterizing small supernumerary marker chromosomes with combination of multiple techniques

Fourteen cases with constitutional small supernumerary marker chromosomes (sSMCs) were assessed by combination of diverse techniques including genome-wide high-resolution chromosomal microarray (CMA), chromosome banding analysis (G banding), fluorescence in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Of the 14 sSMCs, 4 were complex sSMCs composed of genomic materials from more than one chromosome, 7 were simple sSMCs which contain only centromeric and/or pericentromeric regions from individual chromosomes, and the remaining 3 sSMCs contained inverted duplications. CMA precisely defined the breakpoints and genetic contents in 12 of the 14 sSMCs but failed to identify 2 of the 14 sSMCs due to lack of detectable euchromatin. In addition, CMA revealed unexpected genomic abnormalities in 2 cases. FISH techniques were necessary for the determination of the physical location, structure, formation mechanism, mosaic level, and origin of all these sSMCs. Our data emphasize the necessity to combine these methods for comprehensive characterization of sSMCs.     

Nature and implications of supernumerary or accessory chromosomes in neonates

The incidence of supernumerary or accessory human chromosomes in clinically normal and abnormal cases lead to a variety of questions. Thus genetic counselling in such cases is often a difficult task.     

Polymorphism for supernumerary chromosomes in populations of Rana temporaria L

Occurrence of B-chromosomes in four populations of Rana temporaria L. in Minsk, its suburb and Berezinski? biosphere reserve has been studied. The percentage of individuals with B-chromosomes and the average number of B-chromosomes per genome are shown to multiply increase in the population inhabiting for 40 years in the region polluted with waste products. The results obtained are discussed from the standpoint of the action of mechanism for the accumulation of additional chromosomes due to environmental pollution.     

A novel mechanism for the origin of supernumerary marker chromosomes

A ring chromosome 3 and a 47^th chromosome formed by the portions of 3p and 3q distal to the r(3) breakpoints were found in a girl with mental retardation and minor facial anomalies. The supernumerary chromosome 3, rea(3), had a primary constriction inside its 3p portion (3p23) and was consistently stable both in lymphocytes and fibroblasts. In situ hybridization with alphoid probes revealed that the r(3) maintained its wild-type centromere, whereas the rea(3) showed no alphoid-related signals. This case and a similar one recently reported demonstrate that acentric fragments can acquire a new centromere and become stable, and that supernumerary marker chromosomes can also originate by the junction of the acentric portions distal to the centric region forming a ring. The possibility of such a chromosome segregating will depend on its ability to (re)activate a new centromere.     

Germ line-restricted supernumerary (B) chromosomes in Eptatretus okinoseanus.

Cytogenetic studies were performed on two types of Japanese hagfish (Eptatretus okinoseanus) that eliminate about 45% (type A) and 55% (type B) of their DNA from presumptive somatic cells during the differentiation of somatic cells. The observations revealed inter- and intraindividual variations in the number of chromosomes in germ cells of both types of hagfishes. Although the modal number of chromosomes in the germ cells was 54 in both types, the percentage of cells with the modal number was rather low (38.6% [51/132] in five specimens of type A and 22.7% [25/110] in eight specimens of type B). In addition, one of seven type B specimens clearly had a modal number of 62 chromosomes. Another specimen of type B had a bimodal distribution of chromosome numbers, with peaks of 54 and 59 chromosomes. The observation of interindividual variations was supported by data on the amount of DNA in germ cells of type B specimens. However, these variations were rarely observed in somatic cells. These results suggest that supernumerary (B) chromosomes are maintained in germ cells and are eliminated together with some other chromosomes and/or chromatin from somatic cells.     

A stably transmitted pair of translocated supernumerary chromosomes in maize.

A pair of stably transmitted supernumerary chromosomes of unknown source has been found in a maize stock carrying a desynaptic mutant. The presence of the supernumerary chromosome appears to be unrelated to the meiotic mutant, but is believed to have been derived from a translocated B chromosome contaminant. The supernumerary chromosomes carry a segment of a A chromosome in this stock where there appear to be two normal copies of each of the 10 A chromosomes. Thus, this A chromosome segment is present in quadruplicate. Surprisingly, a quadrivalent configuration is formed in most microsporocytes, which involves not only synapsis but also chiasma formation in the A chromosome segments involved in the quadrivalent. This represents a strong preferential pairing of supernumeraries with the normal A chromosome segments. Such nonrandom association and crossing over might provide information on the nature of early homologue alignment at meiosis.     

The effect of supernumerary chromosomes on meiosis in Puschkinia libanotica (Liliaceae)

The presence of the partly heterochromatic supernumerary chromosomes in pollen mother cells of Puschkinia libanotica raises the chiasma frequency in the A chromosome bivalents. The pattern of chiasma distribution along each of the five A bivalents was related to the DNA labelling pattern of mitotic chromosomes. Regions that showed heavy labelling at the end of the DNA synthetic phase had fewer chiasmata than lightly labelled regions. As this relation is the opposite to that found by Rees and Evans in another species we regard any correlation between labelling pattern and chiasma distribution as fortuitous.     

Characterization of supernumerary ring marker chromosomes by fluorescence in situ hybridization (FISH).

Five cases with small supernumerary ring chromosomes are characterized at the molecular level. Routine chromosome banding analysis was insufficient for identification of the ring chromosomes, and none of them was DA/DAPI positive. Fluorescence in situ hybridization utilizing repetitive centromeric probes for all chromosomes has determined that one of these five ring chromosomes originates in each of chromosomes 4, 7, 8, 9, and 20. Chromosome painting with chromosome-specific libraries has confirmed this and excluded the involvement of additional chromosomes in the rearrangements.     

Two supernumerary marker chromosomes, originating from chromosomes 6 and 11, in a child with developmental delay and craniofacial dysmorphism

The interpretation of the significance of marker chromosomes, which can be encountered at prenatal diagnosis, is extremely problematic. Various factors contribute to the difficulty of clarifying the phenotypic risks of supernumerary marker chromosomes, including differences in the size, structure, and origin of marker chromosomes, as well as the occurrence of multiple marker chromosomes of different origin in the same proband. Research on marker chromosomes is currently in a data-accumulation phase. We report the presence of two marker chromosomes, originating from chromosomes 6 and 11, in a child with developmental delay and craniofacial dysmorphism and discuss the related literature.     

Multiple congenital abnormalities in a newborn with two supernumerary marker chromosomes derived from chromosome 14

Pure partial duplication or triplication of the proximal part of chromosome 14 has been reported in only 4 patients. Other individuals with a duplication or triplication of this region have additional chromosome imbalances. We present a new case with a supernumerary marker chromosome in all blood cells and in 35% of the cells an additional smaller marker chromosome. Both markers appeared to be derived from chromosome 14 (del(14)(q21.2) in all cells and del(14)(q11.2) in 35% of the cells). This results in a partial duplication of the proximal region of chromosome 14, combined with a mosaic partial triplication of a smaller segment of the same region. In this paper, we compare the clinical features of this case to those of cases from the literature. Although most of the patients from literature were unbalanced translocation carriers, their clinical features were comparable, except from renal abnormalities.     

Value of silver staining technics for the study of acrocentric ring chromosomes and supernumerary microchromosomes

The silver staining techniques was used to study two cases of ring chromosomes (ring chromosome 15 and ring chromosome 22) and two cases of small extra chromosomes. This technique allows identification of the breakpoints and provides some information about the origin of small extra chromosomes.     

The nature and behaviour of supernumerary chromosomes in the rhizirideum group of the genus Allium

Individuals at various levels of ploidy in three species of Allium (angulosum, nutans and senescens) contain a morphologically uniform B-chromosome. This supernumerary is different in character from other B-types recorded for the genus. In diploids the B divides at second anaphase so that 50% of the pollen grains transmit it. The level of transmission is lower in the pollen of polyploids and still lower on the female side where pre-meiotic elimination occurs in both diploids and polyploids. Despite this, and although no effect of the B could be discerned on germination, all plants examined possessed the B-chromosome.This paper was prepared in the Department of Genetics, University of Birmingham while the author was a recipient of a British Council Scholarship.     

Cytogenetics of collared lemmings (Dicrostonyx groenlandicus). II. Meiotic behavior of B chromosomes suggests a Y-chromosome origin of supernumerary chromosomes

The patterns of synapsis and chiasma formation of the B chromosomes of male collared lemmings (Dicrostonyx groenlandicus) were analyzed by light and electron microscopy and compared to expectations for various hypotheses for the intragenomic origin of supernumerary chromosomes. Pachytene analysis revealed a variety of synaptic configurations including B-chromosome univalents, bivalents and trivalents. In approximately one-half of the pachytene nuclei examined, B chromosomes were in synaptic associations with the normally unpaired portion of the Y chromosome. The B-chromosome configurations at pachynema, including those involving the Y chromosome, were maintained into diakinesis and metaphase I. The meiotic behavior of the B chromosomes was inconsistent with their derivation from centric-fusion products, isochromosome formation, small-autosome polysomy, or the X chromosome. However, the frequent synapsis and apparent recombination between B chromosomes and the Y chromosome implicate this sex chromosome as a possible source of the B chromosomes in collared lemmings.