CHROMOSOMAL ANOMALIES 

The Karyotype A normal male chromosome pattern would be described as:

46,XY. 46 =  total number of chromosomes XY = sex chromosome constitution (XY = male, XX = female). Any further description would refer to any abnormalities or variants found (see following slide for examples).

Classification of chromosomal anomalies Numerical (usually due to de novo error in  meiosis) Aneuploidy 

‐ monosomy ‐ trisomy

Chromosome Number Abnormality Trisomy 21 (47, XX, +21)

47,XX,+21

By Mario Chevrette

Chromosome anomalies • Cause their effects by altering the amounts of products of the  genes involved. – Three copies of genes (trisomies)  = 1.5 times normal amount. – One copy of genes (deletions) = 0.5 times normal amount. – Altered amounts may cause anomalies directly or may alter the balance of  genes acting in a pathway.

Aneuploidy: Nondisjunction

normal disjunction at meiosis 46

1st div. 23

23

n. 18

2nd div. 23

23

23

46 23

Normal zygote

23

After fecondation with normal gamete

Non-disjunction at 1° meiotic division 46

1st div. NON-DISJ. 24

22

n. 18

2nd div. 24

47

24

22

Fecondation with

22

45

23

TRISOMY 18

MONOSOMY 18

Non-disjunction at the 2 nd meiotic division 46

1 st div. 23

23

n. 18

2 nd div. NON DISJ. 24

47

22

Fecondation with normal gamete e

23

23

45

Normal zygotes

23

TRISOMY 18

MONOSOMY 18

Non disjunction is an error at mitosis or meiosis;  Chromosome structure is normal There is no need to control parental chromosomes

Classification of chromosomal anomalies

• Different cell lines (occurs post‐zygotically) • Mosaicism

Mosaic Mechanism of origin: Mitotic non‐ disjunction

Mitotic non-disjunction at 1 st zygote division

46

NON DISJ.

n. 18

47

47

TRISOMY 18

45

47

45

45

MONOSOMY 18

Mitotic non-disjunction at 2 nd zygote division (or later)

46

n. 18 46

46

NON DISG. 46

46

CARIOTIPO NORMALE

47

TRISOMIA 18

45

MONOSOMIA 18

Classification of chromosomal anomalies Numerical (usually due to de novo error in meiosis) Polyploidy

‐ triploidy ‐ tetraploidy

Mechanism of origin:

• Fertilization by two sperms • Persistence of the 2 nd polar globule

Origin of triploidy e tetraploidy

CHIMERA

Chimerism 2 ZYGOTES

46,XX

46,XX n. 7

n. 18

FUSION

46,XX

46,XX

46,XX

EMBRYO - CHIMERA

46,XX

Chimerism Y

46,XX

X

46,XY

n. 2

2 ZYGOTES

FUSION

46,XX

46,XY

46,XX

EMBRYO - CHIMERA

46,XY

Classification of chromosomal anomalies • Structural  • (may be due to de novo error in meiosis or inherited) • Deletions • Duplications • Inversions Translocations

‐ reciprocal ‐ Robertsonian (centric fusion)

The Karyotype: an international description

Total number of chromosomes,   Sex chromosome constitution,   Anomalies/variants. 46,XY 47,XX,+21    47,XXX          69,XXY

Trisomy 21 (Down syndrome) Triple X syndrome Triploidy

45,XX,der(13;14)(p11;q11)   Robertsonian translocation 46,XY,t(2;4)(p12;q12)  Reciprocal translocation 46,XX,del(5)(p25)   Deletion tip of chromosome 5 46,XX,dup(2)(p13p22)    Duplication of part of short arm Chr 2 46,XY,inv(11)(p15q14)    Pericentric inversion chromosome 11 46,XY,fra(X)(q27.3)       Fragile X syndrome 46,XY/47,XXY            Mosaicism normal/Klinefelter syndrome

Deletions

Deletion «del» 1 break

Cri du chat, 5p-

Interstitial deletion «int del» two breaks

Duplication «dup (dir)»

Ring chromosome «r» two breaks

unstable

Isochromosome «i» (monocentric)

Centromeric Misdivision Sir C. D. Darlimgton, 1936, 1940

i dic

Breakage and reunion

Balanced Translocation 46,XY,t(2;4)(p12;q12)  Two breaks

46,XY,t(11;16)(q24;q23)

t (reciprocal)

t ( at meiosis )

N S

Segregation 2:2 N S 2:2 alternate

2:2 adjacent 1

2:2 adjacent 2

Chromosomes 1 and 2 from the 2 nd gamete in dashed line

Segregation 3:1

4 possibilities to segregate >> 3:1 8 different gametes

Chromosomes 1 and 2 from the 2 nd gamete in dashed line

Segregation 4:0

Chromosomes 1 and 2 from the 2 nd gamete in dashed line

complex t 3 breaks

Complex t 4 breaks

Kariotype of the proposita: 46,XX ,t(1,2,4,11) Arrows indicate chromosomes involved in the translocation Dashes on normal chrom. indicate  breakpoints

Translocation: non-random X-inactivation

Distrophin : Allele 1  on inactive X chrom. Allele 2  at breakpoint on  translocated X chrom. Phenotype……..

DMD in female

Translocation

Robertsonian  translocation 45, XY, t(14q21q) Robertsonian translocation Reciprocal translocation

Translocation PAIRING AT MEIOSIS

3:0

Gametes: i) 21/21 ii) ‐‐‐‐‐ Result Trisomy 21   Or Nullisomy 21

inv (paracentric)

inv (pericentric)

inv dup (15, 22 …)