Human Cytogenetics Rooney Pdf 14

Purpose: Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.

Two recent studies that make use of CGH have reported large-scale CNVs in the normal human genome (Iafrate et al. 2004; Sebat et al. 2004). The significance of these genome variations is currently unknown (Carter 2004). The identification of these types of normal CNVs was not within the scope of this study; it is likely that a modification to the CNAT algorithm would be required to detect them. This is because the algorithm used in our study compares copy-number data from the test sample with a reference set; the individuals included in the reference set would be expected to contain normal CNV. According to the TCAG Genomics Variation database (Centre for Applied Genomics), the average size of a CNV is 400 kb, and, with 91% of the genome within 100 kb of a SNP on the 100K arrays, it is highly likely that multiple SNPs would cover each CNV and would theoretically be detectable.

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Medical cytogenetics is the study of human chromosomes under the light microscope and the relationship of chromosomal abnormalities to human diseases, disability, and dysmor-phology. As a discipline, human cytogenetics developed slowly at first throughout the 20th centuary. In the early 1900s, the human chromosome number was believed to be 48 for females with an XX sex chromosome complement, and 47 for males with a single X chromosome. In 1928, Painter suggested that both sexes had 48 chromosomes, but that males had two sex chromosomes, an X and a Y (1). In 1952, Hsu discovered that use of a hypotonic solution swelled cells and separated the chromosomes, making their study much easier (2). This was the first of several technical advances that opened the doors to the clinical evaluation of human chromosomes. Four years later, in 1956, Tijo and Levan, aided by the discovery of hypotonic solution and improved cytogenetic technique, established that the chromosome number in humans was actually 46, not 48 (3).

Down syndrome (DS) is the most common genetic reason for learning disability and congenital malformations in the human population, occurring with an incidence of around 1/600 newborns. It is now almost half a century since the genetic background was identified, i.e. that most people with DS have an extra small chromosome, some of which are mosaics with only a proportion of trisomy 21 (T21) cells, while a minority have the relevant part of chromosome 21 translocated to another chromosome, leading to this type running in families with a substantially increased risk for parental carriers [1].

Changes in human oocyte number during prenatal and postnatal development. There is a very rapid increase in human female germ cell (oocyte) number early during fetal development with a peak at 7 months gestational age, followed by a relatively rapid decline before birth and postnatally before puberty, but a slower depletion during reproductive years until menopause

In summary, we suggest that gonadal T21 mosaicism may be a prevailing constitution in humans, underlying the different types of predisposition for having a child with T21 DS. We presume that for any particular parent this is dependent on the proportion of T21 cells in their adult gonads resulting from the differential delay and selection during oogenesis and spermatogenesis. Thus some women, who are high grade ovarian mosaics, are predisposed to T21 offspring at an early age, but for the low grade majority the delay in T21 oocyte maturation leads to their accumulation within the ovarian reserve and a higher incidence at later reproductive ages. On the other hand, the more efficient apoptotic selection against aneuploid germ cells in testes implies that men are less likely to father a child with DS, although exceptions to this general rule are known as regards some who are high grade testicular mosaics, the first such cases identified already in 1971 [39].

In this study we have, for the first time, documented that T21 ovarian mosaicism is common in normal human female foetuses. T21 mosaicism has also previously been documented in ovaries from adult human females, who have had one or more children with T21 DS (Table 1). Thus, in a total population of 15 human females, where ovarian cells have been investigated in this respect, T21 mosaicism of varying degrees has been found in all. On the basis of these observations, together with the expected implications as regards the maternal age effect, the higher recurrence of DS in younger women, the aberrant maternal meiotic recombination patterns and the low incidence of DS of paternal origin, we suggest that gonadal mosaicism is a prevalent unifying reason for T21 conceptions in the human population.

In this paper we challenge the current dogma that disomic maternal and paternal gametes are most often caused by failure of the two homologs 21 to separate at the first meiotic division, so called primary non-disjunction. Instead we propose that obligatory secondary non-disjunction of three homologs 21, which is the expected outcome of gonadal T21 mosaicism, may constitute a common reason. One relatively straight forward way to obtain further information on this situation would be to count copy number of chromosome 21 at the meiotic metaphase I stage to find out what proportion contain two respectively three copies. To our knowledge no T21 spermatocytes have so far been identified at the metaphase 1 stage in testicular biopsy samples from any men other than those diagnosed as having T21 DS, but this nevertheless requires further study. In particular, there are as far as we are aware no such data available on human oocytes, where collection of a large enough sample of ovulating oocytes presents one of the outstanding hurdles. Further studies in this regard are underway. Obviously more work is also required to find out to what extent gonadal mosaicism does exist for other chromosomes than 21, including those that are of special relevance for common genetic disease in the human population. On another note, we are also wondering if the intriguing species difference as regards constitutional aneuploidy, where it would appear that our own species is much more affected than other mammals, could be caused by more stringent control of embryonic cells divisions and therefore a lower incidence of gonadal aneuploidy mosaicism. Similar studies as we have here reported on chromosome copy number in human foetal ovaries should be straight forward and allow this outstanding question to be readily answered.

Recently, the significant achievement in the field of molecular cytogenetic has brought evidences that demonstrated a higher incidence of chromosomal mosaicism in diseased individuals, i.e. brain diseases [8], and additionally, chromosomal mosaicism is not just a casual finding during cytogenetic analysis, but a more significant biological phenomenon than previously recognized and its roles in genetic diversity, human diseases, abnormal prenatal development are still to be elucidated [10]. In our study we did not perform further analysis for non mosaic monosomy detected by 20 metaphase cells conventional cytogenetic analysis, based on the opinion that extensive searching for 46,XX cells in 45,X karyotype individuals is not necessary, since the detection of a normal cell lineages in fewer than 5 percent of cells does not change the prognosis and management [3]. Interestingly, in our study among cases underwent both karyotyping and FISH there were 7 cases had normal 46,XX or 46,XY karyotypes, but had mosaic or additional cell lineages with monosomy detected using FISH and the level of mosaicism was between 3% to 10%. This can lead to misdiagnosis and is a challenging situation, which may be encountered by clinician and should lead them to be more cautious in facing cases with clinical suspicion of TS, but otherwise normal results of karyotypes. It is still a major problem to interpret mosaicism, especially in cases with low-level mosaicism. Further evaluation to detect hidden 45,X cell line using sex chromosome FISH or other molecular cytogenetic methods should be considered. As proposed by Vorsanova et al. [11] FISH and CGH (comparative genomic hybridization) might be necessary in chromosomal disorders in order to provide higher detection rate of somatic chromosomal mosaicism. If the diagnosis of TS is suspected clinically but the result of routine testing is normal, it is indicated to increase the number of cells counted to 100 and to perform a skin biopsy for fibroblast karyotyping to rule out mosaicism for an abnormal cell lineage [3]. Other group [12] recommended in such cases cytogenetic study of a second tissue (e.g. skin biopsy for cell culture or buccal smear for FISH).

Most of our cases (58.9%) have mosaic 45,X cytogenetic analysis results, which assumed to contribute to the phenotypes diversity found. Many authors believed that mosaicism formations occur during fetal life. Spontaneous somatic chromosomal variations presenting as low level mosaicism can be detected in all somatic cell populations. However, the low-level mosaicism is frequently overlooked, because of unapparent phenotypic effects. On the other hand Yurov et al [13], showed that human developing brain has mosaic nature, being composed of euploid and aneuploid cells, and determined the average aneuploidy frequency as 1.25-1.45% per chromosome with the overall percentage of aneuploidy tending to approach to 30-35% and suggested there is an expected link between developmental chromosomal instability, intercellular/intertissular genome diversity and human brain diseases. Similarly a systematic review and meta analysis [14] on the chromosomal constitution of human preimplantation embryos reported 73% of embryos were mosaic, of which diploid-aneuploid mosaic was the most prevalent type of mosaicism (59%) detected. In view of relationship between the diversity in cytogenetic results and the phenotypes, surely our study samples still need to be explored further using combination of molecular cytogenetic methods. In addition with the use of molecular cytogenetics the possible relationship between genomic variations and monosomy phenotypes will be clarified. be457b7860