L33- Chromosomal Aberrations 24 PDF

49 Chromosomal Aberration (Numerical & Structural) ILOs By the end of this lecture, students will be able to 1. Interpret the different types of chromosomal abnormalities. 2. Differentiate between aneuploidy and polyploidy. 3. Differentiate between balanced and unbalanced karyo...

49 Chromosomal Aberration (Numerical & Structural) ILOs By the end of this lecture, students will be able to 1. Interpret the different types of chromosomal abnormalities. 2. Differentiate between aneuploidy and polyploidy. 3. Differentiate between balanced and unbalanced karyotypes. 4. Correlate the phenotypic outcome with types of chromosomal aberrations. Numerical aberrations Euploidy: The normal number of chromosomes for a species. In humans, the euploid number of chromosomes is 2n (46) in somatic cells and n (23) in gametes. Types of numerical chromosomal abnormalities: A. Polyploidy: It is a condition in which the chromosome number is a simple multiple of a haploid chromosome set. Triploidy:  69 chromosome with XXX or XXY or XYY; there are 3 copies for each chromosome (3n) (Figure 1).  Caused by failure of reduction division in meiosis in an ovum or sperm.  Alternatively it can be caused by fertilization of an ovum by two sperm: this is known as dispermy.  Usually results in early spontaneous miscarriage.  Example: Partial vesicular mole occurs when triploidy results from an additional set of paternal chromosomes, in which placenta is severely malformed and appears as bunch of small vesicles, and the embryo is abnormal. Figure 1. Karyotype from products of conception showing triploidy. Tetraploidy:  92 chromosome with XXX or XXYY; There are 4 copies for each chromosome (4n)  Occurs due to failure of the first cleavage zygotic division resulting in doubling of the chromosome numbers immediately after fertilization (4n).  Very rare and always lethal. Page 1 of 5 B. Aneuploidy It is an abnormal chromosome number due to an extra or missing chromosome but does not involve the whole chromosome set. When the abnormality involves the autosome the abnormal phenotype is more severe than involvement of sex chromosomes. Aneuploidy is caused by: 1. Non-disjunction: failure of homologous chromosomes segregation during meiosis I or failure of segregation of sister chromatids during meiosis II or mitosis. Mostly, it is due to the aging effect on the primary oocyte in old age mothers. 2. Anaphase lag: Failure of chromosome or chromatid to be incorporated into one of the daughter nuclei following cell division, as a result of delayed movement (lagging) during anaphase. Trisomy:  It is the presence of three copies instead of two for an autosome or sex chromosome in an otherwise diploid cell (2n+1) (Figure 2).  The karyotype is describes as (47, sex chromosomes, + the number of the chromosome with an extra copy). Ex: Down syndrome male karyotype (47, XY, +21). Figure 2. Karyotype of Down syndrome. Monosomy:  It is the absence of a single chromosome  Monosomy for an autosome is almost always incompatible with survival to term.  The X chromosome monosomy including Lack of contribution of an X or a Y chromosome results in a (45, X) karyotype, which causes the condition known as Turner syndrome is the only live birth example of monosomy. The phenotype of Turner Syndrome is of a female with close to normal intelligence but may have some learning disability. They are infertile and show some physical features including webbing of the neck, low hairline, as well as short stature. Page 2 of 5 C. Mixoploidy Having two or more genetically different cell lineages within one individual is called mixoploidy. The genetically different cell lineages could arise from the same zygote resulting in mosaicism or may result from fusion of 2 different twin zygotes resulting in chimerism (Figure 3).  Mosaic Down Syndrome occurs when the two chromatids of chromosome 21 fail to separate at the second mitotic division in a human zygote, this would result in the four-cell zygote having two cells with 46 chromosomes, one cell with 47 chromosomes (trisomy 21), and one cell with 45 chromosomes (monosomy 21). It accounts for 1% to 2% of all clinically recognized cases of Down syndrome and usually milder than pure disjunction Down Syndrome.  Dispermic Chimeras: These are the result of double fertilization whereby two genetically different sperms fertilize two ova and the resulting two zygotes fuse to form one embryo. If the two zygotes are of different sex, the chimeric embryo can develop into an individual with true hermaphroditism and an XX/XY karyotype having an ovary and a testicle either as separate organs or as ovitesticle on both sides. Figure 3. Mixoploidy: Mosaicism and Chimerism. Structural Aberrations: It refers to chromosome breakage with subsequent reunion in a different configuration that occurs between homologous chromosomes during crossing over in meiosis or between non- homologous chromosomes in case of abnormal rejoining of broken chromosomes. They can be: 1. Balanced rearrangements: the chromosome complement is complete, with no loss or gain of genetic material. Consequently, balanced rearrangements are generally harmless with the exception of rare cases in which one of the breakpoints damages an important functional gene. However, carriers of balanced rearrangements are often at risk of producing children with an unbalanced chromosomal complement. Page 3 of 5  2. Unbalanced rearrangements: the chromosomal complement contains an incorrect amount of chromosome material and the clinical effects are usually serious. Types of structural chromosomal abnormalities (Figure 4): Deletions (del)  A deletion involves loss of part of a chromosome.  Loss of more than 2% of the total haploid genome will have a lethal outcome. Inversions (inv)  An inversion is a two-break rearrangement involving a single chromosome in which a segment is reversed in position (i.e., inverted).  Inversions are balanced rearrangements that rarely cause problems in carriers unless one of the breakpoints has disrupted an important gene. Insertions (ins)  It occurs when a segment of one chromosome becomes inserted into another chromosome.  If the inserted material has moved from elsewhere in another chromosome then the karyotype is balanced. Otherwise an insertion causes an unbalanced chromosome complement. Duplication (dup) Represent a gain of chromosomal material through production of one or more copies of a gene or region of a chromosome. Figure 4. Structural Chromosomal aberrations. Translocations A translocation refers to the transfer of genetic material from one chromosome to another. 1. A reciprocal translocation:  It is formed when a break occurs in each of two chromosomes of metacentric and submetacentric types with the segments being exchanged to form two new derivative chromosomes (Figure 5). Page 4 of 5   Usually the chromosome number remains 46. 2. Robertsonian translocation:  It results from the breakage of two acrocentric chromosomes (numbers 13, 14, 15, 21, and 22) at or close to their centromeres, with subsequent fusion of their long arms (Figure 5).  The short arms of each chromosome are lost, this being of no clinical importance as they contain genes only for ribosomal RNA, for which there are multiple copies on the various other acrocentric chromosomes.  The total chromosome number is reduced to 45.  Because there is no loss or gain of important genetic material, this is a functionally balanced rearrangement. Figure 5. Receprocal and Robertsonian translocations. Isochromosomes (i) Results from abnormal centeromeric division that is at right angle to the normal separation (The centromere has divided transversely rather than longitudinally) (Figure 6). The most commonly encountered isochromosome is that which consists of two long arms of the X chromosome. Figure 6. Isochromosome. Ring Chromosomes A ring chromosome is formed when a break occurs on each arm of a chromosome leaving two ‘sticky’ ends on the central portion that reunites as a ring (Figure 7). The two distal chromosomal fragments are lost so that, if the involved chromosome is an autosome, the effects are usually serious. Figure 7. Ring chromosome. Page 5 of 5