UoT 2012 Cytogenetics Lesson 2

8/13/2019 UoT 2012 Cytogenetics Lesson 2

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Cytogenetics



Numerical abnormalities of

chromosomes



Numerical abnormalities: Down, Edward, Patau,

Turner, Klinefelter

Structural abnormalities: deletions, ring,

duplications, isochromosomes, inversions,translocations

Mosaicism

X-inactivation: Lyon hypothesis



Down syndrome/Trisomy 21 1:800 (SA)

Edward syndrome/Trisomy 18 1:7900 (live births)

Patau syndrome/Trisomy 13 1:9500 (live births)

Turner syndrome/45,X 1:1500 - 5000 live born

females

Klinefelter syndrome/47,XXY 1:1000 live born males



1 in 800

3 aetiologies:

Extra chromosome 21

47,XY,+21

95% of cases

Robertsonian translocation

46,XY,rob(14;21)(q10;q10)

2-4% of cases

Mosaic trisomy

47,XX,+21/46,XX

1-2% of cases



Maternal Age at Term Risk for T21 Risk for any chr abn

15 1:1578 1:454

25 1:1351 1:475

30 1:909 1:384

35 1:384 1:178

36 1:307 1:148

37 1:242 1:122

38 1:189 1:104

39 1:146 1:80

40 1:112 1:62



Maternal Age at Term Risk for T21 Risk for any chr abn

41 1:85 1:48

42 1:65 1:38

43 1:49 1:30

44 1:37 1:23

45 1:28 1:18



■ Short stature

■ Microcephaly

■ Cleft lip and palate

■ Polydactyly of the hands■ Congenital heart defects

■ 40% of patients die within the 1st few monthsof life and the majority before 1 year of age

■ Management can only be supportive



■ Females with only one X chromosome = XO

■ Only viable monosomy in humans

■ They are short, with a broad chest andwebbed neck

■ They do not undergo puberty or menstruate,and there is a lack of breast development

■ Intelligence is normal and individuals canlead normal lives

■ Single most frequent abnormal karyotypeseen in spontaneous abortions



45,X 55%

46,X with abnormal X 15%

Deletion

Isochromosome

Ring

Mosaic 30%

X/XX

X/XY

X/XXX etc.



■ Males that have two or more X chromosomes inaddition to a Y chromosome.

■ The Y chromosome drives the production of

testosterone ~ development as a male butgonads are underdeveloped and breasts develop.

■ Tall with long limbs.

■ Klinefelter males are usually slow to learn butare not mentally retarded.

■ Testosterone replacement therapy.



Structural abnormalities of

chromosomes



Deletion

Ring chromosome

Duplication

Isochromosome Inversion: paracentric & pericentric

Translocation: Robertsonian & reciprocal



Involves loss of part of a chromosome

Results in monosomy of that chromosomal

segmentClinical effects due to insufficient gene

products

Unmasking of mutant alleles on normal

chromosome



Terminal deletion



Interstitial deletion



Interstitial deletion

46,XY,del(2)(q23q24.2)



Breaks occur in both arms of achromosome

The two broken ends anneal; the two

acentric fragments are lost

Results in double deletion (in p and in q)



Trisomy of duplicated segment

Direct

Inverted



Mirror image chromosome

Loss of one arm with duplication of other

Monosomic for lost arm and trisomic for

isochromosome



Two breaks in one chromosome

The fragment generated rotates 180º and

reinserts into the chromosome 2 types:

Pericentric - involves p and q arm

Paracentric - involves only one arm



Exchange of chromosomal materialbetween two or more chromosomes

Reciprocal

Robertsonian

If no essential chromosome material lost orgenes damaged then the individual isclinically normal

However, there is an increased chance of

chromosomally unbalanced offspring



Involves two chromosomes

One break in each chromosome

The two chromosomes exchange broken segments



Most common structural chromosomeabnormality in humans

Frequency = 1:1000 live births

Involves two acrocentric chromosomes



An individual with 2 or more cell types

originating from a single zygote, differing in

chromosome number or structure

47,XX,+8/46,XX (mosaic trisomy 8)Usually results from non-disjunction during

mitosis in the zygote

Sex chromosome mosaicism is common:

45,X/46,XX/47,XXY etc.



Same amount of X-linked gene productsbetween males and females

Males: One X chromosome

Female: Two X chromosomes

And yet, the mean amounts of gene products of

X-linked genes are the same in males as infemales

HOW?

Through the mechanism of dosage compensation

X inactivation



Proposed by Mary Lyon

In somatic cells of a female, X inactivationoccurs early in embryonic life

Is random

Either paternal or maternal X

Is complete

Is permanent

Is clonally propagated through mitosis



Inactivation is not always random

A structurally abnormal X is preferentially

inactivated, i.e. isochromosome of X

Inactivation is not completeSome genes are known to escape

inactivation (i.e. those with a functional

homolog on the Y)

Inactivation is not permanent

Reversed in development of germ cells

(not passed on to gametes)



Non-disjunction

Numerical abnormalities: Down, Edward,

Patau, Turner, Klinefelter

Structural abnormalities: deletions, ring,duplications, isochromosomes, inversions,

translocations

Mosaicism

X-inactivation: Lyon hypothesis

UoT 2012 Cytogenetics Lesson 2

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