Chromosome abnormalities

Dr Cédric Le CaignecService de Génétique

MédicaleCHU Nantes

1. Chromosome abnormalities or rearrangements

2. Gene defects: mutations

Genetic anomalies

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

Chromosome abnormalities

Different types

Balanced anomalies: associated with a normal phenotype for the majority

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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

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

Constitutional / Acquired

Homogeneous / Mosaic

Chromosome abnormalities

Mit

osi

sM

eio

sis

Birth

Fecundation

Constitutional / Acquired

Homogeneous / Mosaic

Numerical / structural

Balanced Unbalanced

Chromosome abnormalities

Numerical abnormalities

Numerical abnormalities :the ploidy

Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes

Numerical abnormalities : the ploidy

Diploidy (normal somatic cell) : 2 haploïd sets of chromosomes

Polyploidy : more than 2 haploïd sets of chromosomes (ex: triploidy)

Anomaly at fecundation

Triploidy : 69,XXX or 69,XXY or 69,XYY

Tetraploidy : 92,XXYY or 92,XXXX (hemopathies, tumors)

Numerical abnormalities : polyploidy

69,XXX

Numerical abnormalities :example of a triploid cell

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 :

Numerical abnormalities :example of trisomy 21 (autosome)

Numerical abnormalities :example of monosomy X

Mechanisms of the aneuploidies

Non-disjunction in meiosis First division in meiosis I Second division in meiosis II

Post-zygotic mitotic non-disjunction

MI

MII

Mechanisms of the aneuploidies: meiosis I non disjunction

Most often:

homogeneous

anomaly

MI

MII

Mechanisms of the aneuploidies: meiosis II non disjunction

Most often:homogeneous

anomaly

Mechanisms of the aneuploidies

Non-disjunction in meiosis First division in meiosis I Second division in meiosis II

Post-zygotic non-disjunction in mitosis

Most often:mosaics

Mechanisms of the aneuploidies: post-zygotic non-disjunction in

mitosis

Zygote (post

Fecundation)

mat MI MII pat

Trisomy 21 91% 75%Trisomy 18 93% 60%Trisomy 13 88%

45,X 80%47,XXY 53% 47%

Aneuploidies

STRUCTURAL ANOMALIES

Structural anomalies

Balanced

---> Normal phenotype but risk to future offspring Unbalanced

Deletion Duplication Derived chromosome

---> usually associated with abnormal phenotype

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

Structural anomalies

Only one chromosome involved One breakage: terminal deletion

breakageloss neotelomere

del(4)(p15.3)

Terminal deletions (del)

One breakage: terminal deletion

4p deletion

5p deletion :Cri du chat syndrome

Terminal deletions (del)

Structural anomalies

Only one chromosome involved One breakage: terminal deletion Two breakages:one arm: interstitial deletion

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

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

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

rob(13;14)(q10;q10)ou

der(13;14)(q10;q10)

loss

fusion

normal phenotype but clinical consequences

Robertsonian translocations (rob ou der)

45,XX,rob(14;21)(q10;q10)

Loss of the short arm(s) of chromosomes 14 and 21

Normal phenotype

14 21

der (14;21)(q10;q10)

Risk to future offspring ?

50 % ?

Trisomy 14 ?Trisomy 21 ?

pachytene

alternate segregation

pachytene

balanced normal

balanced normal gametes

zygotes

adjacent segregation

trisomy 21

disomy 21

gametes

zygotes monosomy 21

nullosomy 21

miscarriage

46,XY,der(14;21)(q10;q10),+21

trisomy 21

adjacent segregation

monosomy 14

nullosomy 14

miscarriage

trisomy 14

disomy 14

gametes

zygotes

miscarriage

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

der(21;21)(q10;q10) Rarely inherited When inherited: 100% risk of trisomy 21 in the

offspring

Genetic counseling

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

Genetic counseling

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

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

t(6;18)(p24;q21.2)fusion

Translocations (t)Two breakpoints located on two different chromosomes followed by an exchange: reciprocal translocation

Reciprocal translocations

Normal phenotype when balanced

When abnormal phenotype (rarely): Gene interrupted at one of the breakpoint microdeletion or microduplication

Breakpoint anomaly

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

t (11;22)(q23.3;q11.2)

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Reciprocal translocations

Reciprocal translocations46,XX,t(11;22)(q23.3;q11.2)

Electronic microscopyPachytene stage

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

normal gamete balanced gamete

pachytene

Alternate segregation

pachytene

gametes

zygotes

Partial monosomy and trisomy

trisomy 11q dist.monosomy 22q dist.

trisomy 22q dist.monosomy 11q dist.

Adjacent 1 segregation

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 ?

Robertsonian translocations Involve two acrocentric chromosomes

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

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

rob(13;14)(q10;q10)ou

der(13;14)(q10;q10)

loss

fusion

normal phenotype but clinical consequences

Robertsonian translocations (rob ou der)

45,XX,rob(14;21)(q10;q10)

Loss of the short arm(s) of chromosomes 14 and 21

Normal phenotype