chromosome abnormalities dr cédric le caignec service de génétique médicale chu nantes
TRANSCRIPT
![Page 1: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/1.jpg)
Chromosome abnormalities
Dr Cédric Le CaignecService de Génétique
MédicaleCHU Nantes
![Page 2: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/2.jpg)
1. Chromosome abnormalities or rearrangements
2. Gene defects: mutations
Genetic anomalies
![Page 3: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/3.jpg)
Level of resolution
Chromosomal band:Chromosomal band:5-10 Mb5-10 Mb
Genome: Genome: 3x103x1099 bases bases
ATGCACTGATGAATGCATGCAATATGCACTGATGAATGCATGCAAT
A gene: about A gene: about 20 kb20 kb
From 1 bFrom 1 b to 1000 b to 1000 b Molecular level Molecular level
Cytogenetic level
Cytogenetic level
![Page 4: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/4.jpg)
Chromosome abnormalities
Different types
Balanced anomalies: associated with a normal phenotype for the majority
11 22
![Page 5: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/5.jpg)
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
Chromosome abnormalities
![Page 6: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/6.jpg)
At birth 0.6 à 0.9% of the newborns carry a chromosomal anomaly
Third trimester miscarriages: 5% of the fetuses carry a chromosomal anomaly
First trimester miscarriages: 60% of the fetuses carry a chromosomal anomaly
high pressure of selection during fetal development
Chromosome abnormalities
![Page 7: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/7.jpg)
Constitutional / Acquired
Homogeneous / Mosaic
Chromosome abnormalities
![Page 8: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/8.jpg)
Mit
osi
sM
eio
sis
Birth
Fecundation
![Page 9: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/9.jpg)
Constitutional / Acquired
Homogeneous / Mosaic
Numerical / structural
Balanced Unbalanced
Chromosome abnormalities
![Page 10: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/10.jpg)
Numerical abnormalities
![Page 11: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/11.jpg)
Numerical abnormalities :the ploidy
Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes
![Page 12: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/12.jpg)
Numerical abnormalities : the ploidy
Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes
Polyploidy : more than 2 haploïd sets of chromosomes (ex: triploidy)
![Page 13: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/13.jpg)
Anomaly at fecundation
Triploidy : 69,XXX or 69,XXY or 69,XYY
Tetraploidy : 92,XXYY or 92,XXXX (hemopathies, tumors)
Numerical abnormalities : polyploidy
![Page 14: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/14.jpg)
69,XXX
Numerical abnormalities :example of a triploid cell
![Page 15: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/15.jpg)
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)
Numerical abnormalities :
![Page 16: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/16.jpg)
Numerical abnormalities :example of trisomy 21 (autosome)
![Page 17: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/17.jpg)
Numerical abnormalities :example of monosomy X
![Page 18: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/18.jpg)
Mechanisms of the aneuploidies
Non-disjunction in meiosis First division in meiosis I Second division in meiosis II
Post-zygotic mitotic non-disjunction
![Page 19: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/19.jpg)
MI
MII
Mechanisms of the aneuploidies: meiosis I non disjunction
Most often:
homogeneous
anomaly
![Page 20: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/20.jpg)
MI
MII
Mechanisms of the aneuploidies: meiosis II non disjunction
Most often:homogeneous
anomaly
![Page 21: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/21.jpg)
Mechanisms of the aneuploidies
Non-disjunction in meiosis First division in meiosis I Second division in meiosis II
Post-zygotic non-disjunction in mitosis
![Page 22: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/22.jpg)
Most often:mosaics
Mechanisms of the aneuploidies: post-zygotic non-disjunction in
mitosis
Zygote (post
Fecundation)
![Page 23: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/23.jpg)
mat MI MII pat
Trisomy 21 91% 75%Trisomy 18 93% 60%Trisomy 13 88%
45,X 80%47,XXY 53% 47%
Aneuploidies
![Page 24: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/24.jpg)
STRUCTURAL ANOMALIES
![Page 25: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/25.jpg)
Structural anomalies
Balanced
---> Normal phenotype but risk to future offspring Unbalanced
Deletion Duplication Derived chromosome
---> usually associated with abnormal phenotype
![Page 26: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/26.jpg)
Structural anomalies
Only one chromosome involved One breakage: terminal deletion Two breakages: one arm: interstitial deletion
paracentric inversiontwo arms: pericentric
inversion ring chromosomeisochromosome
Two chromosomes involved Robertsonian translocation Reciprocal translocation
![Page 27: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/27.jpg)
Structural anomalies
Only one chromosome involved One breakage: terminal deletion
![Page 28: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/28.jpg)
breakageloss neotelomere
del(4)(p15.3)
Terminal deletions (del)
One breakage: terminal deletion
![Page 29: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/29.jpg)
4p deletion
5p deletion :Cri du chat syndrome
Terminal deletions (del)
![Page 30: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/30.jpg)
Structural anomalies
Only one chromosome involved One breakage: terminal deletion Two breakages:one arm: interstitial deletion
![Page 31: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/31.jpg)
Two breakpoints
Interstitial deletions
Two breakpoints on the same chromosome arm and loss of the chromosome region between: interstitial deletion
loss of the chromosome region between
![Page 32: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/32.jpg)
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
![Page 33: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/33.jpg)
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
![Page 34: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/34.jpg)
rob(13;14)(q10;q10)ou
der(13;14)(q10;q10)
loss
fusion
normal phenotype but clinical consequences
Robertsonian translocations (rob ou der)
![Page 35: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/35.jpg)
45,XX,rob(14;21)(q10;q10)
Loss of the short arm(s) of chromosomes 14 and 21
Normal phenotype
![Page 36: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/36.jpg)
14 21
der (14;21)(q10;q10)
Risk to future offspring ?
50 % ?
Trisomy 14 ?Trisomy 21 ?
![Page 37: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/37.jpg)
pachytene
![Page 38: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/38.jpg)
alternate segregation
pachytene
balanced normal
balanced normal gametes
zygotes
![Page 39: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/39.jpg)
adjacent segregation
trisomy 21
disomy 21
gametes
zygotes monosomy 21
nullosomy 21
miscarriage
![Page 40: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/40.jpg)
46,XY,der(14;21)(q10;q10),+21
trisomy 21
![Page 41: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/41.jpg)
adjacent segregation
monosomy 14
nullosomy 14
miscarriage
trisomy 14
disomy 14
gametes
zygotes
miscarriage
![Page 42: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/42.jpg)
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 %
Genetic counseling
![Page 43: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/43.jpg)
der(21;21)(q10;q10) Rarely inherited When inherited: 100% risk of trisomy 21 in the
offspring
Genetic counseling
![Page 44: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/44.jpg)
der(13;14)(q10;q10) frequent (~ 1/1200) low risk: trisomy 13 ( ~ 1%)
Genetic counseling
![Page 45: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/45.jpg)
45,XY,der(13;14)(q10:q10)
![Page 46: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/46.jpg)
Structural anomalies
Only one chromosome involved One breakage: terminal deletion Two breakages: one arm: interstitial deletion
paracentric inversiontwo arms: pericentric
inversion ring chromosomeisochromosome
Two chromosome involved Robertsonian translocation Reciprocal translocation
![Page 47: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/47.jpg)
t(6;18)(p24;q21.2)fusion
Translocations (t)Two breakpoints located on two different chromosomes followed by an exchange: reciprocal translocation
![Page 48: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/48.jpg)
Reciprocal translocations
Normal phenotype when balanced
When abnormal phenotype (rarely): Gene interrupted at one of the breakpoint microdeletion or microduplication
Breakpoint anomaly
![Page 49: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/49.jpg)
46,XX,t(11;22)(q23.3;q11.2)
![Page 50: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/50.jpg)
t (11;22)(q23.3;q11.2)
11 22
Reciprocal translocations
![Page 51: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/51.jpg)
Reciprocal translocations46,XX,t(11;22)(q23.3;q11.2)
Electronic microscopyPachytene stage
![Page 52: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/52.jpg)
Different modes of segregations
segregations 2:2 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
![Page 53: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/53.jpg)
normal gamete balanced gamete
pachytene
Alternate segregation
![Page 54: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/54.jpg)
pachytene
gametes
zygotes
Partial monosomy and trisomy
trisomy 11q dist.monosomy 22q dist.
trisomy 22q dist.monosomy 11q dist.
Adjacent 1 segregation
![Page 55: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/55.jpg)
![Page 56: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/56.jpg)
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 ?
![Page 57: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/57.jpg)
Robertsonian translocations Involve two acrocentric chromosomes
![Page 58: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/58.jpg)
1 2 3 4 5
6 7 8 9 10
11 12 13 14 15
16 17 18 X Y
19 20 21 22
Among the autosomes, 5 pairs of acrocentric chromosomes : 13, 14, 15, 21 and 22
Among the autosomes, 5 pairs of acrocentric chromosomes : 13, 14, 15, 21 and 22
![Page 59: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/59.jpg)
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
![Page 60: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/60.jpg)
rob(13;14)(q10;q10)ou
der(13;14)(q10;q10)
loss
fusion
normal phenotype but clinical consequences
Robertsonian translocations (rob ou der)
![Page 61: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/61.jpg)
45,XX,rob(14;21)(q10;q10)
Loss of the short arm(s) of chromosomes 14 and 21
Normal phenotype
![Page 62: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/62.jpg)
![Page 63: Chromosome abnormalities Dr Cédric Le Caignec Service de Génétique Médicale CHU Nantes](https://reader036.vdocuments.us/reader036/viewer/2022062312/551b9a48550346a10a8b5de0/html5/thumbnails/63.jpg)