Chromosomal Abnormalities Tutorial Session 2024/2025 (PDF)

Tutorial session 2024/2025 Chromosomal Aberrations (Abnormalities)  Learning Objectives 1- Mention the most common causes of chromosomal abnormalities. 2- list the types of chromosomal abnormalities. 3- Enumerate the causes of aneuploidy. 4- Describe different typ...

Tutorial session 2024/2025 Chromosomal Aberrations (Abnormalities)  Learning Objectives 1- Mention the most common causes of chromosomal abnormalities. 2- list the types of chromosomal abnormalities. 3- Enumerate the causes of aneuploidy. 4- Describe different types of numerical abnormalities. 5- Describe different types of structural abnormalities. 6- How to diagnose chromosomal abnormalities?  Chromosomal Aberrations (Abnormalities) ------------------------------------------------- Def: It means disorder involving morphological or numerical alteration in single or multiple chromosomes, affecting autosomes, sex chromosomes, or both. - Numerical aberrations: There is abnormality in the number of chromosomes. - Structural aberrations: There is abnormality in the structure of chromosomes..Causes increasing the risk of chromosomal aberrations: Environment: Exposure to radiation (X-rays). Chemical agents: formaldehyde, pesticides, food preservatives & tobacco. Cytoytoxic drugs: cholchicine, tetracyclines Maternal age: Pregnancy in old age: increase the risk of non-disjunction. Presence of chromosomal imbalance in the parents or in their families (family tendency). Medical conditions: Autoimune diseases and hypothyroidism. Infection with German measles that causes fragmentation of chromosomes.  Chromosomal aberrations Numerical aberrations Structural aberrations A-Aneuploidy B-Polyploidy 1- Deletion (-/+) ch (s) extra set (s) of ch. 2- ring chromosome 3- inversion. I -Trisomy - Triploidy (3n) 4 -Translocation A- trisomy of autosome: - Tetra-ploidy (4n) 5- Insertion Down syndrome (trisomy 21), - Penta-ploidy (5n) -Edward syndrome (trisomy18) 6 -Isochromosome -Patau syndrome (trisomy 13). 7- Duplication B-trisomy of sex chromosome 8- Dicentric ch. -Klinefelter syndrome (47, - XXY) 9- Fragile ch. -super female (47, XXX), -super male (47, XYY). II-Monosomy A- momsomy of autosome: incompatible with life B- Monosomy of sex- chromosome: Turner syndrome; 45, XO Numerical Chromosomal aberrations A-Aneuploidy  A-ANEUPLOIDY (abnormal ploidy) Def: It means variation in chromosome number range from addition or loss of one or more chromosomes. 1- Monosomy (2n-1) means the loss of single chromosome (presence of one copy of a particular chromosome instead of two) as in A- Monosomy of autosome: - Autosomal monosomy is rarely observed in spontaneously aborted fetuses or in live births. - All complete autosomal monosomies are not viable. - Can survive in mosaic forms. B- Monosomy of sex chromosome: Turner syndrome; 45, XO - In order to survive and develop embryo needs at least one X chromosomes. 2- Trisomy (2n+1): means possessing three copies of a particular chromosome instead of the normal two copies (disomy). There is gain of one extra chromosome. A-Trisomy of autosomes: - Most autosomal tri-somies are also lethal except some notable exceptions as in: - Down syndrome (trisomy 21) = mongolism - Edward syndrome (trisomy 18), - Patau syndrome (trisomy 13). B-Trisomy of sex chromosomes : as in - Klinefelter syndrome (47, XXY), - Super female (47, XXX), - Super male (47, XYY).  Causes of aneuploidy A- Nondisjunction: An accident of meiosis or mitosis in which a pair of homologous chromosomes (during meiosis I) or a pair of sister chromatids (during mitosis or meiosis II) fail to separate at anaphase. - Gaining a single chromosome, in addition to its pair (s) will result in daughter cell (s) having as defect that is referred to as trisomy. - The deletion of a chromosome in a daughter cell is referred to as monosomy. Forms of Non-disjunction: 1- Primary non-disjunction: Failure of separation between two homologous chromosomes (bivalent chromosomes) during meiotic (I) division. This results in one daughter cell with 24 ch and one cell with 22 ch. The second meiotic division results in four abnormal cells. 2- Secondary non-disjunction: Failure of two 2 sister chromatids to separate at the centromere during the meiotic (II) division or in mitosis. This results in 2 normal and 2 abnormal daughter cells in meiosis, and 2 daughter cells are abnormal in mitosis. 3- Mosaicism: If the non-disjunction occurs during mitosis after some normal mitotic divisions (failure of separation between sister chromatids) The results in that the cells of the fetus have more than one line (karyotype), one normal 46 , others may be 47 or 45. abnormal meiotic I abnormal meiotic II division division results in 4 results in 2 normal and 2 abnormal cells abnormal cells B- failure of duplication: Anaphase lag One chromatid (s- chromosome) fails to duplicate during S-phase. C- Anaphase lag= simple loss: Chromosomal loss via micronucleus formation due to failure of a chromosome to align during metaphase or lagging to move in anaphase.  I- Trisomy of chromosomes  Trisomy of autosome Down syndrome: - Down syndrome is caused by an error in cell division “nondisjunction.” - Nondisjunction results in an embryo with three copies of chromosome 21 instead of the usual two. Prior to or at conception, a pair of 21st chromosomes in either the sperm or the egg fails to separate. As the embryo develops, the extra chromosome is replicated in every cell of the body.  Trisomy of autosome Occurs to non-disjunction of chromosomes 21 Karyogram of male trisomy 21 (Down syndrome; 47, XY, +21).  Trisomy of autosome Karyogram of female trisomy 18 (Edward syndrome; 47, XX, +18) Karyogram of male trisomy 13 (Patau syndrome; 47, XY, +13).  Trisomy of sex chromosome Klinefelter syndrome: - Cells contains 47 chromosome - The karyotype is (47, XXY). - Occurs due to early non-disjunction of X chromosome in the first meiotic division of the oocyte. The ovum with extra X chromosome is fertilized with normal sperm having Y chromosome, giving ovum with 47, XXY from its divisions, all the somatic cells will have the same abnormality. - Males with Klinefelter syndrome have Barr body ( + X chromosome). - Characters: mental retardation, small testis, long child, large breasts and widely separated nipples. Multiple X syndrome (Super female, XXX): - 2 sex chromatin (2 Barr bodies) due to extra X chromosome. - Occurs as the same mechanism as klinefelter syndrome, but the patient phenotype is female. Presents with increased height and risk of learning disabilities, delayed development of speech, language, and motor skills and weak muscle tone.  Trisomy of sex chromosome Karyogram of trisomy sex chromosome (Klinefelter syndrome; 47, XXY)  Trisomy of sex chromosome. Karyogram of trisomy sex chromosome (super female; 47, XXX)= multiple X syndrome Karyogram of trisomy sex chromosome (super male; 47, XYY) II- Monosomy of chromosomes  Monosomy of sex- chromosomes Turners syndrome: - Cells with 45 chromosomes. - No Barr body due to missing X chromosome. - Occurs due to non-disjunction of the sex chromosomes meiotic division in oogenesis, or spermatogenesis. - Features; short female, mental retardation, limb edema, primary amenorrhea, undeveloped ovaries.  Monosomy of sex- chromosomes (Turner Ꞩ) Karyogram of sex-monosomy (Turner syndrome; 45, XO).  B-POLYPLOIDY Def: It is a defect of a genome level; affecting the total haploid set (N) - Triploidy: is a term applied when the cell contains 3 chromosomes of each member Similarly, tetraploidy, pentaploidy, polyploidy. Fig. Karyogram of triploidy; 69, XXY. Causes of numerical chromosomal abnormality: Spindle apparatus defects: There is paralysis of the spindle apparatus results in failure of cytokinesis. Abnormal separation of polar bodies: failure of the second polar body to be extruded from the fertilized ovum with subsequent fusion with the male and female pronuclei lead to the formation of triploid zygote (causing polyploidy) Abnormalities during oogenesis or spermatogenesis, resulting in an abnormal oocyte or spermatozoon with a double chromosome complement (46, XX) instead of a haploid complement (23, X). Di-spermy or fertilization of a normal egg by two normal sperm (causing polyploidy) Drugs affecting microtubule system as colchicine and vinblastine. Virus infection as rubella virus of German measles. B-Polyploidy  B-POLYPLOIDY Polyploidy arise when a rare mitotic or meiotic catastrophe affecting the total haploid set (N), causing the formation of gametes that have a complete set (or more) of duplicated homologous chromosomes. Karyogram of triploidy (69,XXX) Karyogram of tetraploidy (92, XXYY) Causes of polyploidy chromosomal abnormality: Non-disjunction. Spindle apparatus defects: There is paralysis of the spindle apparatus results in failure of cytokinesis. Abnormal separation of polar bodies: failure of the second polar body to be extruded from the fertilized ovum with subsequent fusion with the male and female pronuclei lead to the formation of triploid zygote. Di-spermy or fertilization of a normal egg by two normal sperm. Drugs affecting microtubule system as colchicine and vinblastine. Virus infection as rubella virus of German measles.  NB: Endoreduplication: - Is a special case of tetraploidy. There are two sequential DNA replications In S phase. Cell enters division containing 92 d chromosomes. - Each chromosome pair appears to have another homologous pair in close apposition to it. Fig: endoreduplication result of two sequential DNA replications. Structural Chromosomal Aberrations  II- STRUCTURAL ANOMALIES - It results from Chromosomal breaking with or without subsequent rejoining into different configurations. - Mostly due to: radiation, chemicals, drugs, viruses. Two types are identified: A- The aberration is called balanced if the chromosome has the normal complement of genetic information. B- The aberration is called unbalanced if there is addition or loss of the genetic information. 1-deletion(del): It is a loss of any part of a Chromosome (missing information). Types: a- Terminal: - If the breakage is single: (the chromosome loses the terminal end ) b- Interstitial: - If there are 2 breaks at the same chromosome: (loss of the interstitial fragment and fusion at the break sites) - If the deleted part lacks a centromere (acrocentric) it will be lost in the next division. Examples of Interstitial deletion: Wolf-Hirschhorn syndrome: it is a partial deletion of the short arm of chromosome 4. Features: microcephaly, squint, mental retardation, hypotonia. --------------------------------------- Cri Du Chat syndrome: It is large deletion of the short arm of chromosome 5. Features: Low birth wt, high pitched cat cry, congenital heart disease, mental retardation c- Ring chromosome: - It is a special type of deletion that occurs when there are 2 breaks at the 2 distal ends of the same chromosome forming sticky ends that unite to form a ring. (the small parts at the ends are deleted). - Ring chromosome is usually lost resulting in monosomy. Ring chromosome 14; female Ring chromosome 15; female (46, XX, r14) (46, XX, r15)  2- Translocation: - It is a double breakage followed by the transfer of a chromosomal segment carrying genetic material to another non-homologous chromosome. The process requires the breakage of both chromosomes and the exchange of the segments. Two types: 1- Reciprocal translocation. 2- Ropertosonian translocation. a) Reciprocal translocation: - Breakage and exchange of the genetic material distal to breaks between non- homologous chromosomes (but not in acrocentric chromosomes) - As in Philadelphia chromosome (ch 9 and 22) - Half of the long arm of chromosome 22 breaks and is translocated into chromosome 9, tiny part of chromosome 9 is also translocated into chromosome no 22. - The person has 46 chromosomes - leads to chronic myeloid leukemia. Philadelphia chromosome→ reciprocal translocation; 9, 22 Burkitt's Lymphoma→ reciprocal translocation; 8, 14 b) Robertsonian translocation: Much more common. - It arises from breaks at or near the centromere in two acrocentric non-homologous chromosomes with cross-fusion of the products. - Loss of the short arms of the two chromosomes and subsequent fusion of the two long arms at their centromeric regions forming a single large metacentric chromosome. - The person has 45 chromosomes instead of the usual 46. - Chromosomes 14 and 21 are the most frequently involved.  3- Inversion Def: two breaks within a single chromosome where the segment is reversed in position. Types: a) Para-centric inversion: two breaks occur in a single arm, and the inverted segment does not involve the centromere. b) Peri-centric inversion: two breaks occur in the chromosome, on either side of the centromere, so the inverted segment includes the centromere and changes its position.  4- Insertion Insertion occurs when a segment of one chromosome is translocated and inserted into: - another non-homologous chromosome (inter-chromosome insertion). This happens if there are two breaks in one chromosome and a single break in the other. - or into a different region of the same chromosome (intra-chromosomal insertion). N.B: INSERTIONS ARE A TYPE OF TRANSLOCATION: sometimes the expression “insertional translocation” is used 5- Iso-chromosome : Mirror image chromosome (2p’s or 2q’s) - It is an abnormal chromosome that has a deletion of one arm with duplication of the other (duplication deficiency). -arms of the chromosome are mirror images of each other. - Occurs when a normal chromosome divides transversely instead of longitudinally during anaphase.  6- Duplication (addition): - It is the presence of two copies of a segment of a chromosome. - It leads to the presence of a double dose of genes. -Duplication is more common and less harmful than deletion. -The extra piece is joined either: a- within the chromosomal material. b- as an extra piece.  7- Di-centric chromosome The dicenteric chromosome contains two centromeres. - It is formed through the breakage and fusion of two non-homologous chromosomal segments, each with a centromere, resulting in the loss of acentric fragments (lacking a centromere) and the formation of dicentric fragments - -It is unstable because it is torn apart during mitosis and its parts are divided between the two daughter cells. Dicentric chromosome , 8  9- Fragile chromosome -The name comes from an unusual narrow place on the X chromosome that can be seen in a microscope; it is called a fragile site. -Fragile chromosome is susceptible to chromosome breakage. After Down syndrome, the second most frequent genetic cause of mental retardation is fragile X chromosome.  How is chromosomal abnormalities are diagnosed? II-During pregnancy I-Before birth will provide accurate information III-After birth in detecting Down syndrome. - Prenatal screening tests Amniocentesis – - physical signs of the 1-blood test of the birthing A small amount of amniotic fluid syndromes during a physical parent’s blood is obtained for examination with a exam. – 2- ultrasound needle inserted into the - To confirm the diagnosis, (e.g.: signs of Down syndrome abdomen. your baby’s provider may like extra fluid behind your -Chorionic villus sampling – perform a blood test called baby’s neck). A small sample of the placenta is a karyotype test, FISH analyzed which is obtained from technique, or banding the cervix or abdomen. technique. -Percutaneous umbilical blood sampling (cordocentesis) - A tiny sample of blood is taken from the umbilical cord for analysis.  Diagnostic tests during pregnancy Percutaneous umbilical Amniocentesis Chorionic villus sampling blood sampling  Quiz time 1. The chromosome segments are reversed from 3. Which of the following syndromes is a end to end structural chromosomal anomaly…. a- Duplication a- Down syndrome b- Deletion b- Wolf-Hirschhorn syndrome c- Inversion c- Supermale syndrome. d- Translocation d- Turner syndrome. 2- Cri-du-chat syndrome is a genetic disorder that represents a case of ………………. 4- Para-centric inversion….. a- Duplication a- involves centromere in the broken area. b- Deletion b- is a numerical chromosomal abnormality c- Inversion c- involves one break in one chromosome. d- Translocation d- involves two breaks occurring in the single arm of chromosome.  References JUNQUEIRA,S Basic Histology: Atlas and Text by Anthony L. Mescher https://drive.google.com/file/d/1EYyTFKo15GnLxRASgZS6-kt- EMYW8ssD/view?usp=sharing Textbook of Histology by Leslie P Gartner https://drive.google.com/file/d/1Co74V1K35z77LHgS-NAtIwBj4OZF7Py- /view?usp=sharing Histology: a text and atlas: with correlated cell and molecular biology/Michael H. Ross, Wojciech Pawlina https://drive.google.com/file/d/1q1lpkOWNJNLXpkRcmIHvBvm_YYHHIynY/view?usp= sharing THANK YOU