1. Chromosome abnormalities
Dr Cédric Le Caignec
Service de Génétique Médicale
CHU Nantes

2. Genetic anomalies 1. Chromosome abnormalities or rearrangements
2. Gene defects: mutations

3. Level of resolution Molecular level Cytogenetic level
ATGCACTGATGAATGCATGCAAT
A gene: about 20 kb
From 1 b to 1000 b
Molecular level
Cytogenetic level
Chromosomal band:
5-10 Mb
Genome: 3x109 bases

4. Chromosome abnormalities
Different types
Balanced anomalies: associated with a normal phenotype for the majority 11 22

5. Chromosome abnormalities
Different types
Balanced anomalies: associated with a normal phenotype for the majority
Unbalanced anomalies: with a gain or a loss of genetic material usually with abnormal phenotype

6. Chromosome abnormalities
At birth 0.6 à 0.9% of the newborns carry a chromosomal anomaly
 high pressure of selection during fetal development
Third trimester miscarriages: 5% of the fetuses carry a chromosomal anomaly
First trimester miscarriages: 60% of the fetuses carry a chromosomal anomaly

7. Chromosome abnormalities
Constitutional / Acquired
Homogeneous / Mosaic

8. Meiosis
Fecundation
Mitosis
Birth

9. Chromosome abnormalities
Constitutional / Acquired
Homogeneous / Mosaic
Numerical / structural
Balanced
Unbalanced

10. Numerical abnormalities

11. Numerical abnormalities : the ploidy
Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes

12. Numerical abnormalities : the ploidy
Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes
Polyploidy : more than 2 haploïd sets of chromosomes
(ex: triploidy)

13. Numerical abnormalities : polyploidy
Anomaly at fecundation
Triploidy : 69,XXX or 69,XXY or 69,XYY
Tetraploidy : 92,XXYY or 92,XXXX (hemopathies, tumors)

14. Numerical abnormalities : example of a triploid cell
69,XXX

15. Numerical abnormalities :
Diploidy (normal somatic cell) : 2 haploïd chromosome sets
Polyploidy : more than 2 haploïd chromosome sets
(ex: triploidy)
Aneuploidy :
Gain of one (or more) chromosome (trisomy)
Loss of one (or more) chromosome (monosomy)

16. Numerical abnormalities : example of trisomy 21 (autosome)

17. Numerical abnormalities : example of monosomy X

18. Mechanisms of the aneuploidies
Non-disjunction in meiosis
First division in meiosis I
Second division in meiosis II
Post-zygotic mitotic non-disjunction

19. Mechanisms of the aneuploidies: meiosis I non disjunctionMI
MII
Most often:
homogeneous
anomaly

20. Mechanisms of the aneuploidies: meiosis II non disjunction
Most often:
homogeneous
anomaly MI
MII

21. Mechanisms of the aneuploidies
Non-disjunction in meiosis
First division in meiosis I
Second division in meiosis II
Post-zygotic non-disjunction in mitosis

22. Mechanisms of the aneuploidies: post-zygotic non-disjunction in mitosis
Zygote (post
Fecundation)
Most often:
mosaics

23. Aneuploidies mat MI MII pat Trisomy 21 91% 75% Trisomy 18 93% 60%
45,X %
47,XXY % %

24. STRUCTURAL ANOMALIES

25. Structural anomalies Balanced
---> Normal phenotype but risk to future offspring
Unbalanced
Deletion
Duplication
Derived chromosome
---> usually associated with abnormal phenotype

26. Structural anomalies Only one chromosome involved
One breakage: terminal deletion
Two breakages: one arm: interstitial deletion
paracentric inversion
two arms: pericentric inversion ring chromosome
isochromosome
Two chromosomes involved
Robertsonian translocation
Reciprocal translocation

27. Structural anomalies Only one chromosome involved
One breakage: terminal deletion

28. Terminal deletions (del)
One breakage: terminal deletion
loss
neotelomere
breakage
del(4)(p15.3)

29. Terminal deletions (del)
4p deletion
5p deletion :
Cri du chat syndrome

30. Structural anomalies Only one chromosome involved
One breakage: terminal deletion
Two breakages: one arm: interstitial deletion

31. Interstitial deletions
Two breakpoints on the same chromosome arm and loss of the chromosome region between: interstitial deletion
loss of the chromosome region between
Two breakpoints

32. Anomalies de structure
Only one chromosome involved
One breakage: terminal deletion
Two breakages: one arm: interstitial deletion
paracentric inversion
two arms: pericentric inversion ring chromosome
isochromosome
Two chromosome involved
Robertsonian translocation: centric fusion

33. Robertsonian translocations
Involve two acrocentric chromosomes
Breakpoints located at the centromere or close to
Loss of the short arms
Loss of a centromere
Karyotype with 45 chromosomes
Consequences in meiosis

34. Robertsonian translocations (rob ou der)
fusion
loss
rob(13;14)(q10;q10) ou
der(13;14)(q10;q10)
normal phenotype but clinical consequences

35. 45,XX,rob(14;21)(q10;q10)
Loss of the short arm(s) of chromosomes 14 and 21
Normal phenotype

36. Risk to future offspring ?
der (14;21)(q10;q10)
Trisomy 14 ?
Trisomy 21 ?
50 % ? 14 21

37. pachytene

38. alternate segregation
pachytene
alternate segregation
balanced
normal
gametes
zygotes
balanced
normal

39. adjacent segregation trisomy 21 gametes zygotes monosomy 21
disomy 21
gametes
zygotes
monosomy 21
nullosomy 21
miscarriage

40. 46,XY,der(14;21)(q10;q10),+21
trisomy 21

41. adjacent segregation trisomy 14 gametes zygotes monosomy 14 disomy 14
miscarriage
monosomy 14
nullosomy 14
miscarriage

42. Genetic counseling der(14;21)(q10q10)
the majority of the familial trisomy 21
(1/2 de novo ; 1/2 inherited)
different risk when maternally or paternally inherited
Maternally inherited : trisomy 21 risk: 15 %
Paternally inherited : trisomy 21 risk : 2 %

43. Genetic counseling der(21;21)(q10;q10) Rarely inherited
When inherited: 100% risk of trisomy 21 in the offspring

44. Genetic counseling der(13;14)(q10;q10) frequent (~ 1/1200)
low risk: trisomy 13 ( ~ 1%)

45. 45,XY,der(13;14)(q10:q10)

46. Structural anomalies Only one chromosome involved
One breakage: terminal deletion
Two breakages: one arm: interstitial deletion
paracentric inversion
two arms: pericentric inversion ring chromosome
isochromosome
Two chromosome involved
Robertsonian translocation
Reciprocal translocation

47. Translocations (t) fusion t(6;18)(p24;q21.2)
Two breakpoints located on two different chromosomes followed by an exchange: reciprocal translocation
fusion
t(6;18)(p24;q21.2)

48. Reciprocal translocations
Normal phenotype when balanced
When abnormal phenotype (rarely):
Gene interrupted
at one of the breakpoint
microdeletion or
microduplication
Breakpoint anomaly

49. 46,XX,t(11;22)(q23.3;q11.2)

50. Reciprocal translocations
t (11;22)(q23.3;q11.2) 11 22

51. Electronic microscopy
Reciprocal translocations
46,XX,t(11;22)(q23.3;q11.2)
Electronic microscopy
Pachytene stage

52. Different modes of segregations
alternate
adjacent 1
adjacent 2
segregations 3:1
4 possible combinations
segregation 4:0
Number of gametes in theory
16 possible combinations but not equal

53. Alternate segregation
normal gamete
balanced gamete
pachytene

54. Partial monosomy and trisomy
Adjacent 1 segregation
pachytene
gametes
Partial monosomy and trisomy
zygotes
trisomy 11q dist.
monosomy 22q dist.
trisomy 22q dist.
monosomy 11q dist.

56. You see a 25 years old patient for sterility without any anomalies
You see a 25 years old patient for sterility without any anomalies. His karyotype is 45,XY,rob(14;21)(q10;q10)
How do you interpret this result ?

57. Robertsonian translocations
Involve two acrocentric chromosomes

58. Among the autosomes, 5 pairs of acrocentric chromosomes : 13, 14, 15, 21 and 226 7 8 9 10 11 12 13 14 15 16 17 18 X Y 19 20 21 22

59. Robertsonian translocations
Involve two acrocentric chromosomes
Breakpoints located at the centromere or close to
Loss of the short arms
Loss of a centromere
Karyotype with 45 chromosomes
Consequences in meiosis

60. Robertsonian translocations (rob ou der)
fusion
loss
rob(13;14)(q10;q10) ou
der(13;14)(q10;q10)
normal phenotype but clinical consequences

61. 45,XX,rob(14;21)(q10;q10)
Loss of the short arm(s) of chromosomes 14 and 21
Normal phenotype