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Cytogenetics II Structural chromosomal aberrations RNDr Z.Polívková Lecture No 432 - course : Heredity.

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Presentation on theme: "Cytogenetics II Structural chromosomal aberrations RNDr Z.Polívková Lecture No 432 - course : Heredity."— Presentation transcript:

1 Cytogenetics II Structural chromosomal aberrations RNDr Z.Polívková Lecture No course : Heredity

2 Causes of structural aberrations: external mutagens (except Robertsonian translocations) origin in: G1,S, G2, mitosis, meiosis Structural CHA: unbalanced – loss or gain of chromosomal material balanced – abnormal rearrangement without loss or gain of chromosomal material

3 Unbalanced Deletion (del) = partial monosomy – terminal - interstitial - break and loss of chromosomal segment in G1 - unequal crossing over in meiosis - segregation of balanced aberration in meiosis → unbalanced product Duplication (dup) = partial trisomy - duplication in S phase, - insertion of a segment of sister chromatid - unequal crossing over in meiosis, - segregation of balanced aberration in meiosis Ring chromosome (r) – partial monosomy of segments distal to breaks on short and long arms - reunion of broken chromosome to a ring formation

4 Dicentric chromosome (dic) – abnormal chromosome with 2 centromeres - 2 breaks of 2 chromosomes or 2 chromatids and reunion of broken ends, in G1, G2 Isochromosome – partial monosomy of one arm and partial trisomy of other arm - misdivision (transverse splitting) of centromere in MI, MII, mitosis Additional marker chromosome (+mar) small chromosome of unknown origin – supernumerrary - if heterochromatic – mostly without clinical consequences Detection of origin of marker chromosome – FISH method

5 Balanced CHA: Robertsonian translocation (Rob t)– fusion of 2 acrocentrics near centromere – origin in meiosis-by nonhomologous pairing and exchange similar to crossing over Reciprocal translocation (rcp t) – reciprocal exchange of 2 segments of 2 chromosomes – in G1,G2 – breaks and exchanges Inversion (inv) - pericentric – 2 breaks on p (short arms) and q (long arms) and reconstitutions of inverted segment between breaks – in G1 - paracentric – 2 breaks on one arm and reconstitutions of inverted segment between breaks – in G1 Insertion – segment removed from 1 chromosome is inserted into another chromosome – 3 breaks rearrangement

6 Deletions terminal interstitial break, (2 breaks) and loss of terminal (interstitial) segment in G1

7 Terminal deletion Xp – short stature

8 Terminal deletion Xq -steriliy

9 Origin of interstitial deletion and duplication unequal crossing over between homologs or unequal exchange between sister chromatids

10 Origin of interstitial deletion and duplication insertion of a segment of sister chromatid in G2

11 Interstitial deletion 16q – congenital abnormalities + MR

12 Interstitial deletion 16q

13 Interstitial duplication 2q – congenital abnormalities + MR

14 dup2q

15 Ring chromosome breaks on p and q and joining of broken ends

16 Ring chromosome X – patient with TS – mosaic with 45,X

17 Dicentric chromosome translocation dicentric isodicentric + acentric fragment breaks on both chromatids and chromatid reunion Breaks of 2 chromosomes and fusion i nactivation of 1 centromere = pseudodicentric of centric (and acentric) fragmens SS

18 dicentric (pseudodicentric) chromosome X from 2 cells, C-band

19 Isochromosome missdivision of centromere – loss of one arm and duplication of the second arm – i(q)

20 patient with clinical features of TS but fertile

21 Robertsonian translocation break on 2 acrocentrics near centromere and fusion of long arms (fused product of short arms is lost) – origin usually in meiosis

22 balanced Robertsonian translocation

23 unbalanced Robertsonian translocation - DS

24 Origin of reciprocal translocation chromatid exchange in G2 breaks and exchange in G1 chromatid breaks on 2 chromosomes and exchange

25 t(4;6) reciprocal translocation-balanced

26 der(6)t(4;6) derivative chromosome 6 – congenital abnormalities + MR

27 t(4;6) der (6)

28 Origin of inversions pericentric paracentric 2 breaks on p and q 2 breaks on one arm inversion and joining of inverted segment

29

30 pericentric inversion 6 - balanced

31 recombinant chromosome 6 – congenital abnormalities + MR

32 Inversion 6 recombinant chromosome 6

33 paracentric inversion 1q balanced

34 Origin of insertion insertion of interstitial segment of one chromosome to the site of break on another chromosome - in G1

35 ins(10;14) - insertion of a part of 14q to 10q - balanced

36 ins(10;14)

37 CCR(1;6;14;18) - complex chromosomal rearrangement - balanced

38 Risk of balanced structural aberration: Carrier of balanced structural aberration usually without clinical signs risk of unbalanced aberration in progeny

39 + Carrier of balanc. Rob.t normal Nonhomologous Rob t gametes after MI Zygotes after S phase transl.trisomy carrier of balanc.t normal monosomy 21 1/3 1/3 1/3 letal theoretic risk

40

41

42 Theoretic risk of translocation form of Down syndrome (DS) in parent - carrier = 1/3 Actual risk: 10-15% for woman - carrier of t21/14 2% for man - carrier of t21/14 For other nonhomologous translocations lower risks (21/22, 13/14) Mechanisms of selection against chromosomal anomaly: some types of segregation are less probable ( influenced by morphology of rearranged chromosomes) in ♀ meiosis= cell with CHA more probably become polar body in ♂ meiosis – irregularities in pairing of rearranged chromosomes → poor sperm development → oligospermia, azoospermia gamete with CHA – selectional disadvantage in fertilisation (in sperm) selection against abnormal zygote = spontaneous abortion

43 46,XX 22,X ,X t21/21 23,X 45,XX t21/21 23,X t21/21 23,X t21/21 23,Y 23,X t21/21 22,X ,XY t21/21 46,XY t21/ % (DS or abortion) 0% Homologous Rob t 21/21 (13/13) de novo origin risk Carrier of balanced Robt Normal karyotype

44 translocation form of DS (homologous fusion 21/21)

45 Reciprocal translocation N1 T1 T2 N2 T2 N1 N2 T2 in M I prophase - kvadrivalent

46 Balanced reciprocal translocation Segregation 2:2 Types of segregation: T1,T2 - N1, N2 = alternate → balanced + normal gametes T1, N2 - T2, N1 = adjacent 1 unbalanced gametes T1, N1 - T2, N2 = adjacent 2 with duplication a deletion Empiric risk: 10% for woman - carrier 2-5% for man - carrier But risk is dependent on the type of translocation (length of translocated segments) Segregation 3:1 = tercial trisomy One of the translocated chromosomes is small and its trisomy is compatible with life

47 t(4;6)der(6)

48 Pericentric inversion – mechanism of meiotic recombination crossing over inside meiotic loop→ a) duplication of p and deletion of q or b) duplication of q and deletion of p a) b)

49

50 Risk of meiotic recombination in a carrier of pericentric inversion depends on the length of inverted segment in average: for woman – carrier - 10% for man - carrier - 5%

51 Paracentric inversion Crossing over inside loop → dicentric chromosome and acentric fragment

52 Origin of interstitial deletion and duplication Unequal crossing over outside of meiotic loop – in both inversions

53 Consequences of balanced aberrations Segregation of unbalanced genome (affected child, abortion) Sterility (esp.in men) Effect on phenotype – MR, anomalies (rcp t, inv de novo) Balanced CHA with phenotypic effect : 1.Small deletion 2.Small mosaic? 3. Inactivation of gene (site of break inside gene) → manifestation of recessive alleles on homologous chromosome (described in X/A translocations) 4.Posion effect: incorrect gene order, impairment of gene regulation, neighbourhood of heterochromatine (spreading effect)

54 Consequences of unbalanced aberrations congenital malformations mental retardation Partial trisomy – less severe than partial monosomy of the same segment Lack of chromosomal material = more severe then excess Degree of expression – depends of the length of trisomic and monosomic segment and its gene content

55 Indications to chromosomal examination !!! Postnatal (from peripheral blood – lymphocytes): 1.Specific phenotype (MD……) 2.Psychomotoric retardation (PMR), growth retardation, dysmorpfic features, congenital malformations, small stature in girls, oedema in newborns (TS) 3.Dysfertility (repeated spontaneous abortions, sterility – chromosomal examination in both partners) 4.Amenorrhea, delayed puberty, genital malformations

56 Indication of prenatal cytogenetic examination From cells of amniotic fluid, chorionic villi, fetal blood 1.Increased maternal age (≥ 35 years) 2.Patological values of biochemical markers 3.Abnormality on ultrasound 4.One parent is a carrier of balanced chromosomal aberration

57 Indication of prenatal cytogenetic examination From cells of amniotic fluid, chorionic villi, fetal blood 1.Increased maternal age (≥ 35 years) 2.Patological values of biochemical markers 3.Abnormality on ultrasound 4.One parent is a carrier of balanced chromosomal aberration

58 presentation supplementary text to cytogenetics Thompson &Thompson: Genetics in medicine, 7th ed. Chapter 5: Principles of clinical cytogenetics Chapter 6: Clinical cytogenetics: Disorders of the autosomes and the sex chromosomes + informations from presentation


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