Chromosomes and Their Disorders II PDF

‫بسم هللا الرحمن الرحيم‬ CHROMOSOMES AND THEIR DISORDERS By Dr.Noha Issa Ass. Prof. and consultant of medical genetics Department of Genetic Medicine Faculty of medicine KAU Dr.med . Wisam Habhab Ass. Prof. and clinical molecular geneticist, Department of Genetic Medicine Faculty of Medicine KAU...

‫بسم هللا الرحمن الرحيم‬ CHROMOSOMES AND THEIR DISORDERS By Dr.Noha Issa Ass. Prof. and consultant of medical genetics Department of Genetic Medicine Faculty of medicine KAU Dr.med . Wisam Habhab Ass. Prof. and clinical molecular geneticist, Department of Genetic Medicine Faculty of Medicine KAU Objectives ✓Classify chromosomal abnormalities ✓Discuss the abnormalities on a given karyotype for a common condition ✓Outline the clinical abnormal karyotype implications of Types of chromosomal anomalies Abnormalities of chromosomes either: ✓Numerical chromosomal abnormalities ✓Structural chromosomal abnormalities ✓Different cell lines(mixoploidy): mosaicism Numerical chromosomal abnormalities Polyploidy ◦ The basic set of chromosomes is the haploid set (n) which is the number of chromosomes present in the gametes n=23. ◦ The diploid set (2n) is the number of chromosomes present in the normal somatic cells 2n= 46 Numerical chromosomal abnormalities ◦ Aneuploidy ◦ The loss or gain of one or more chromosome/s. ◦ Occurs in 3-4% of pregnancies ◦ Monosomy ◦ Presence of one copy of a chromosome (loss of one) ◦ Turner Syndrome 45,X ◦ Trisomy ◦ Presence of three copies of a chromosome (addition of one) ◦ 47,XY,+21 (Three copies of 21). ◦ Polyploidy ◦ The gain of one or more haploid sets of chromosomes ◦ Triploidy (3n) ◦ Presence of three set of chromosomes ◦ 69,XXY ◦ Tetraploidy (4n) ◦ Presence of four sets of chromosomes ◦ 92, XXYY Numerical chromosomal abnormalities ❖Triploidy most frequently result from: ✓ fertilization by two sperms (dispermy) ✓ fertilization of abnormal diploid sex cell (ova 2n )with a normal sex cell ( sperm n) or vise versa e.g Retention of polar body ❖Tetraploidy could result from the failure of the zygote to divide after it replicate its chromosomes. Numerical chromosomal abnormalities . 69,XXY Triploidy Numerical chromosomal abnormalities . 92,XXYY Numerical Chromosome Abnormalities Aneuploidy Most aneuploidy patients have either trisomy (3 instead 2) or less often monosomy (1instead of 2). Both could have severe phenotypic consequences. Numerical Chromosome Abnormalities ➢Trisomy for a whole chromosome is rarely compatible with life except : trisomy 21, trisomy 13, trisomy 18, triple X female, Klinefelter syndrome. ➢Monosomy for an entire chromosome is almost always lethal. Turner syndrome is an important example. 47,XX,+21 Standard Down Syndrome Clinical characteristics ◦ MR ◦ Craniofacial Brachycephaly, a flat occiput ,microcephaly, ◦Congenital heart disease, e.g. ventricular septal defect. ◦Duodenal atresia, imperforate anus ◦ Umbilical hernia, and cryptorchidism. ◦Liability to autoimmune disorders,e.g. Thyroditis ◦Increase risk of leukemia (20 times than normal) 47,XX,+13 Patau Syndrome 47,XY,+13 Patau Syndrome Patau sndrome 47,XY,+13 Mental and growth retardation Hypotonia, Holoprosencephaly Microcephaly, sloping forehead, scalp defect, forebrain defect Eye: microphthalmia, anophthalmia and colobomata of iris cleft lip and / or palate Polydactyly(postaxial) Heart: VSD,ASD,PDA 47,XX,+18 Edward Syndrome 47,XY,+18 Edward Syndrome 45,X Turner Syndrome Turner Syndrome Aneuploid y Trisomy 21 Trisomy 18 Trisomy 13 Monosomy X 47,X XY Klinefelter Syndrome Klinefelter Syndrome Numerical Chromosome Abnormalities The causes of aneuploidy are not well understood, but the most common chromosomal mechanism is meiotic nondisjunction. This refers to the failure of the chromosomes to disjoin properly during one of the two meiotic divisions. Numerical Chromosome Abnormalities The consequences of nondisjunction during meiosis I and II are different. If the error occurs during meiosis I the gamete contain both paternal and maternal members of the pair. If it occurs during meiosis II, the gamete with the extra chromosome contains both copies of either the paternal or maternal chromosome. Numerical Chromosome Abnormalities Nondisjunction can occur in a mitotic division after the formation of a zygote. If this happens at an early cleavage division, mosaicism may result. Numerical Chromosome Abnormalities Mosaicism ➢Two or more chromosome complement are present in an individual ➢Mosaicism may be either numerical (most common type) or structural. It results from: Post-zygotic non-disjunction: both sister chromatids go to one pole--- 2n+1 / 2n-1 Anaphase lag: one sister chromatid lag and lost --- 2n / 2n-1 Abnormalities of Chromosome Structure It results from chromosome breakage followed by reconstitution in an abnormal combination. These may be balanced if the chromosome set has the normal complement of chromosomal material, or unbalanced if there is additional or missing material. Abnormalities of Chromosome Structure Balanced Unbalanced The chromosome set has the normal There is loss or gain of complement ,no loss or gain chromosomal material Don’t usually have phenotypic effect But they can pose a threat to the offspring The phenotype is likely to be abnormal ▪ Insertion ▪ Inversion ▪ Translocations: Reciprocal or robertsonian ▪ ▪ ▪ ▪ ▪ ▪ Deletions Duplications Marker chromosomes Ring chromosomes Isochromosomes Fragile site Symbols Used in Describing a Karyotype Term explanation example p Short arm q Long arm cen centromere del deletion 46,XX,del(1)(q21) dup duplication 46,XY,dup(13)(q14q22) i isochromosome 46,X,i(X)(q10) r Ring chromosome 46,XX,r(21) t translocation 46,XY,t(2;4)(q21;q21) rob Robertsonian 46,XY,rob(14;21)(q10;q10),+21 inv inversion 46,XX,inv(9)(p12q12) der derivatives 46,XY,der(14;21)(q10;q10),+21 mar marker 47,XY,+mar ins insertion Unbalanced Rearrangements Deletions They involve loss of a chromosome segment resulting in chromosome imbalance. A deletion may be terminal or interstitial. 46,XX,del(5)(P15) Cri-du-chat syndrome or (5p- syndrome ) Deletion 5p15 Cri-du-chat 46,XX,del(5)(p15) - Cat like cry (hypoplasia of larynx) - Moon face, hypertolerism - Microcephaly , micrognathia - Mental and motor delay 46,XY,del(4)(p16.1) Wolf-Hirschhorn syndrome or 4p- syndrome 46,X,del(X)(q22.1) Duplications They are less harmful than deletions. Due to partial trisomy, a chromosomal imbalance occurs leading to phenotypic abnormalities. Dup(7)(q21.1q21.3) 46,XY,dup(16)(q12.1q22) Isochromosome ➢Is a chromosome in which one arm is missing and the other duplicated in a mirror image fashion. ➢Thus a person with 46, chromosomes and an isochromosome has a single copy of one arm and a triple copy of the other . The most common isochromosome is that for the X chromosome in some cases of turner syndrome. 46,X,i(X)(q10) Turner syndrome Ring chromosome ➢Formed when a chromosome undergoes two breaks and the broken ends of the chromosome reunite in a ring structure. ➢If the centromere is within the ring, a ring chromosome would be expected to be mitotically stable. Ring chromosome 46,X,r(x) Turner syndrome Chromosomal abnormalities in turner syndrome ◦ Numerical: ➢45,X ◦ Structural chromosomal abnormalities : ➢E.g. : 46,X,r(X) 46,X,i(Xq) 46,X,del(X)(q21) Balanced Rearrangements Insertions A segment removed from one chromosome is inserted into a different chromosome, either in its usual orientation or inverted . Inversions ➢Can occur when a single chromosome undergoes 2 breaks and is reconstituted with the segment between the breaks inverted. ➢2 types: ✓Paracentric inversions do not centromere ✓pericentric involve the centromere. include the Inversions ➢An inversion doesn’t usually cause a phenotypic abnormality in carriers as it is balanced. Its significance is for the progeny, producing abnormal gametes that lead to abnormal offspring. Translocations ❑Reciprocal translocations (rcp) ❑Robertsonian translocation (rob) Translocations ➢Reciprocal translocations result from breakage of nonhomologous chromosomes with reciprocal exchange of the broken off segment. ➢Such translocations are harmless but they are associated with a high risk of unbalanced gametes and abnormal progeny 46,XY,t(1;7)(q23.2;q36) Translocations ✓Robertsonian translocation involves 2 acrocentric chromosomes that fuse near the centromere and lose their short arms. ✓Balanced robertsonian translocation: Chromosomal number is 45 but practically the genome is that of 46 chromosomes. ✓Unbalanced robertsonian translocation: chromosomal number is 46 but the genome is that of 47 chromosomes. ✓chromosome which is made of the long arms of the 2 chromosomes is called derivative chromosome. Balanced female carrier: 45,XX,der(21;21)(q10;q10) 45,XX,rob(21;21) Down syndrome: 46,XY, +21,der(21;21)(q10;q10) 46,XY,+21,rob(21;21)(q10;q10) 46,XY,der(14;21) (q10;q10),+21 46,XY,rob(14;21) (q10;q10) ,+21 Translocation Down syndrome ✓ Down Syndrome (trisomy 21) due to: 1-Non-disjunction : (47,XX,+21) (47,XY,+21) 2-Translocation e.g: 46,XX,+21,rob(21;21)(q10;q10) 46,XY,rob(14;21)(q10;q10),+21 3-Mosaics e.g 47,XY,+21[15]/46,XY[5] Translocations. ✓ Down syndrome : Recurrence Risk for next pregnancy due to nondisjunction : 1% + the maternal age risk Risks in Robertsonian translocation Translocations. ✓ The female carrier of either a 13q21q or a 14q21q Robertsonian translocation runs a risk of approximately 10-15% for having a baby with Down syndrome, whereas for male carriers the risk is 1% to 3%. ✓ In case of a carrier of a 21q21q Robertsonian translocation. All gametes will be either nullisomic or disomic for chromosome 21. ✓ Consequently, all pregnancies will end either in spontaneous miscarriage or in the birth of a child with Down syndrome. 46,XY,rob(14;15)(q10;q10) How to describe chromosomal abnormalities? ✓ Chromosome report reading 46,XY,t(3;8)(p21;q23) : How to describe chromosomal abnormalities? ✓ Chromosome report reading 46,XY,t(3;8)(p21;q23) : Male with a reciprocal translocation between chromosome 3 and chromosome 8 involving short arm of chromosome 3 at region 2 band 1 and long arm of chromosome 8 at region 2 band 3 How to describe chromosomal abnormalities? ✓ Chromosome report reading 46,XX,inv(9)(p11q12) How to describe chromosomal abnormalities ✓ Chromosome report reading 46,XX,inv(9)(p11q13) Female karyotype with pericentric inversion of chromosome 9 in which breakage and reunion have occurred between bands 9p11 and 9q13. Reference ❑ ❑ ❑ https:// images.google.com Google Images. The most comprehensive image search on the web. Emery's Elements of Medical Genetics 16th edition 2020 by Turnpenny and Ellard 78