Structural Chromosomal Aberrations PDF

Structural Chromosomal 3 Aberrations by Dr.Ezat Mersal Enlist different forms of structural chromosomal aberrations Understand the underlying mechanisms of structural aberrations Mention some clinical syndromes related to structural aberr...

Structural Chromosomal 3 Aberrations by Dr.Ezat Mersal Enlist different forms of structural chromosomal aberrations Understand the underlying mechanisms of structural aberrations Mention some clinical syndromes related to structural aberrations Interpret some abnormal forms of human karyotypes  wei's Insil % 1994 1950 © 2015 John Wiley & Sons, Inc. All rights reserved. Term Explanation Example p Short arm q Long arm cen Centromere del Deletion 46,XX,del(1)(q21) dup Duplication 46,XY,dup(13)(q14) fra Fragile site i Isochromosome 46,X,i(Xq) inv Inversion S 46,XX,inv(9)(p12q12) ish In-situ hybridization r Ring 46,XX,r(21) t Translocation 46,XY,t(2;4)(q21;q21) Tip of arm; e.g., pter ter Terminal or end or qter / Mosaicism 46,XY/47,XXY Sometimes used after a chromosome arm in text to + or − 46,XX,5p– indicate © 2015 John gain Wiley or loss of & Sons, Inc.part of that All rights chromosome reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  Relativelycommon  Simple breakage followed by rapid healing by reunion of the 2 sticky ends of chromatids. © 2015 John Wiley & Sons, Inc. All rights reserved.   Also defined as partial monosomy  Caused by chromosome break followed by loss of a segment of chromosome due to no rapid healing.  Type: short 1. Terminal: only one break, usually includes telomere 2. Interstitial: 2 breaks in the same arm, loss of the segment in-between, reunion of the breakpoints:- Wolf syndrome: interstitial deletion in short arm of chromosome no 4. del 4p Cri du chat syndrome: interstitial deletion in short arm of chromosome no 5. del 5p Ring chromosome: 2 terminal breaks, one on each arm of the chromosome (p & q), the telomeres are deleted(telomere dysfunction) with subsequent reunion of the ends in a ring form © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  High pitched cat like cry is the most prominent clinical feature in newborn at time of birth in the hospital  Ear malformations  Nose: broad & depressed(flat)  Eye: widely set, slanting  Small receding mandible  Small head  Heart defects © 2015 John Wiley & Sons, Inc. All rights reserved.  Intrachromosomal rearrangement in which a segment of chromosome between 2 breaks is reversed end to end (rotated /flipped 180).  Two Types: 1. Pericentric: if the 2 breaks, one on either side of the centromere centromere index will change 2. Paracentric: if the 2 breaks are on one side of the centromere No change in the centromere index © 2015 John Wiley & Sons, Inc. All rights reserved.  Also defined as partial trisomy  It means extra piece of a chromosome or even an entire chromosome.  It is opposite to deletion  It occurs due to replication errors within one chromatid or unequal crossing over between homologous chromosomes. © 2015 John Wiley & Sons, Inc. All rights reserved.  A segment of a chromosome dissociates and reattaches to a different, non- homologous chromosome.  It can be benign or detrimental.  Types: 1. Reciprocal translocations: o There is no gain or loss of genetic information, so these are usually benign. o Example: Philadelphia chromosome (Ch 22 & 9 translocation) © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  , 4. 9  Also called centric fusion / whole arm translocation  Most frequent (1/1000 newborn) structural Is y Jes aberration.  Occurs between acrocentric chromosomes i.e. 13, 14, 15, 21, 22.  Example: down syndrome (translocation variant) © 2015 John Wiley & Sons, Inc. All rights reserved.  : 00 40 © 2015 John Wiley & Sons, Inc. All rights reserved.  Three genetic mechanisms of down syndrome An extra whole (trisomy) or partial (translocation) copy of chromosome number 21. © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  Trisomy  Maternal age is related to nondisjunction or mosaicism but not translocation.  Hereditary component (passed from parent to child through the genes) is not relevant in nondisjunction & mosaicism.  Hereditary is relevant in 1/3 cases of down syndrome due to translocation which constitute about 1% of all cases of down syndrome. © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  · I' - - - so assis vie set & Chromosomal Translocation ↑ Malignancy Mechanism of Oncogenesis Expression of the myc oncogene (normally on chromosome 8), under t(8;14) Burkitt lymphoma the control of the immunoglobulin (Ig) gene promoter (normally on chromosome 14) Follicular Control of the antiapoptotic gene bcl-2 (normally on chromosome 18) t(14;18) lymphoma by the regulators of the Ig gene (chromosome 14) Mantle cell t(11;14) lymphoma Aberrant expression of cyclin D Chronic The bcr-abl fusion protein results from the translocation between t(9;22) myelogenous chromosomes 9 and 22. leukemia Acute Results in a mutant form of the retinoic acid receptor that blocks white t(15;17) myelogenous blood cell differentiation leukemia © 2015 John Wiley & Sons, Inc. All rights reserved.   Structuralchromosomal rearrangement in which 3 breaks occurs in 2 different in (heterologous) chromosomes. One segment · is deleted from one chromosome and added to the other. © 2015 John Wiley & Sons, Inc. All rights reserved.  number of breaks © 2015 John Wiley & Sons, Inc. All rights reserved. © 2015 John Wiley & Sons, Inc. All rights reserved.  Definition: An unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other i.e. the chromosome consists of two copies of either the long (q) arm or the short (p) arm (chromosome composed of 2 P identical arms).  Mechanism: centromere misdivision during mitosis or meiosis Transverse splitting (division) of the q metaphase chromosome instead of being longitudinal. It may occur in submetacentric chromosomes & X  Abbreviation: i (17q) means isochromosme number17 containing 2 long q arms © 2015 John Wiley & Sons, Inc. All rights reserved.  A 10-year-old girl was admitted to the pediatric department complaining of short stature. Physical examination revealed her height to be < 3% on the percentile curve by age for girls. She had low set ears and a low-posterior hairline. Ultrasound imaging revealed horse shoes kidneys and streak ovary. Chromosomal analysis was done and her karyotype was shown below. XO What is your probable diagnosis? a) Klinfelter syndrome b) Turner syndrome c) Down syndrome d) Edwards syndrome ze © 2015 John Wiley & Sons, Inc. All rights reserved. A 28-year-old man, married 3 years ago, was referred to andrology outpatient clinic complaining of infertility. Physical examination revealed abnormally tall patient with feminine hair distribution, enlarged breast. Local genital examination revealed small sized penis and testicular atrophy. The andrologist asked the patient to seek genetic consultation for exclusion of any chromosomal anomalies. Which investigation of the following is recommended by the genetic consultant? a) Chromosomal analysis b) Semen analysis c) PCR d) Hormonal profile  The most probable diagnosis of this patient is: a) Trisomy of sex chromosome (47, XXY) b) Trisomy of autosomes (47, 21) c) Monosomy of sex chromosome (45, XO) d) Trisomy of sex chromosome (47, XXX) © 2015 John Wiley & Sons, Inc. All rights reserved. A 40 years old pregnant women gave rise to a newborn with several knots of the umbilical cord wrapped around the neck. The newborn was resuscitated rapidly and the cord knots were cut. The newborn got recovered and weak mewing cat like crying was observed. The health care provider suspected a genetic problem rather than traumatic element. The underlying genetic mechanism for this genetic disorder is: a) Reciprocal translocation of p21 b) Nonreciprocal translocation of p21 c) Deletion of p5 > cri du chat syndrome - d) Inversion of p5 © 2015 John Wiley & Sons, Inc. All rights reserved. Under certain circumstances ( X-ray exposure), a fragment of a chromosome can break off and lead to some forms of chromosomal abnormalities:- % 4  If the broken off fragment reverses its orientation and reattaches to the same - 944455159 position on the original chromosome Chromosomal inversion. 5Js5 > - % S i ·  If the fragment detaches from the chromosome and does not reattach to the same original chromosome Chromosomal deletion.  If the fragment instead attaches to the nearby homologous chromosome Chromosomal duplication.  If the detached fragment moves and attaches to a non-homologous chromosome Chromosomal translocation. © 2015 John Wiley & Sons, Inc. All rights reserved.  Basic genetics : a human approach / BSCS. Dubuque, IA, Kendall/Hunt Pub. Co., c1999. 147 p. QH431.B305 1999  Genes, ethnicity, and ageing. Edited by Lincoln H. Schmitt, Leonard Freedman, Rayma Pervan. Nedlands, Australia, Centre for Human Biology, University of Western Australia ; Singapore, River Edge, NJ, World Scientific, c1995. 100 p.QH455.G45 1995  Genetic polymorphisms and susceptibility to disease. Edited by M. S. Miller and M. T. Cronin. New York, Taylor & Francis, 2000. 266 p.  GENETIC ANALYSIS AN INTEGRATED APPROACH Mark F. Sanders , John L. Bowman Second edition 2015 ISBN 978 0-321-94890-8 (student edition) www.pearsonhighered.com  Boundless Biology: Modern Understandings of Inheritance https://courses.lumenlearning.com/boundless- biology/  Anthony JF Griffiths, William M Gelbart, Jeffrey H Miller, and Richard C Lewontin (1999): modern genetic analysis