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EMS- gim > L6- Chromosomal Basis of Inheritance > Flashcards

L6- Chromosomal Basis of Inheritance Flashcards

1
Q

What is cytogenetics

A

Study of chromosomes

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2
Q

What do conventional cytogenetics look at?

A
  • Metaphase chromosome analysis

G-banding

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3
Q

What do Molecular cytogenetics look at?

A

-Cytogenetic analysis at the molecular resolution at all stages of the cell cycle – DNA or in situ

FISH
Microarray CGH
Next generation sequencing (NGS)
MLPA
QF-PCR
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4
Q

At what stage of the cell cycle are chromosomes most visible?

A

Chromosomes most visible in metaphase in mitosis

Molecular cytogenetics is able to detect at any phase

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5
Q

Stages of Mitosis?

A 
Interphase
prophase
metaphase
anaphase
telophase

then cytokinesis

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6
Q

Features/parts of a chromosome?

A

p arm on top
q arm bottom
telomere part at each end of chromosome
centromere at in the middle

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7
Q

Two types of cytogenetic abnormality

A

1- structural

2-numerical

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8
Q

How do cytogenetic abnormalities produce an abnormal phenotype?

A 
Dosage effect (gain or loss)
Loss > deleterious than excess

Disruption of a gene
Breakpoint
Inappropriate activation/inactivation

Effect due to the parental origin
Genomic imprinting

Position effect
A gene in a new chromosomal environment functions inappropriately

v. Unmasking of recessive disorder

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9
Q

Numerical chromosome abnormality

A

Diploidy = 2 copies of each chromosome

  1. Aneuploidy = gain (trisomy) or loss (monosomy)
  2. Polyploidy = gain whole sets (triploidy or tetraploidy)
  3. Mosaicism = diploidy & aneuploidy
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10
Q

Origins of numerical abnormality

A
  1. Gametogenesis - meiosis
  2. Fertilisation
  3. Early cleavage (post-zygotic non-disjunction)
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11
Q

Learn stages of Meiosis!

A

Figure it out and learn it!

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12
Q

Meiotic errors- what is Non-disjunction?

A
  • Failure of chromosome or chromatid separation
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13
Q

Clinical features of Trisomy 21 - Down’s Syndrome (Meiotic errors)

A 
Head
Eyes: upward slanting; brushfield spots
Nose: Small
Ears: abnormally shaped/low set 
Tongue: protruding
General – flat face, brachycephalic, short neck 
Neurological
Learning disabilities (mild to moderate IQ 30-60)
Hands and feet
single palmar crease
short broad hands
5th finger clinodactyly
wide gap (sandal gap) between the 1st & 2nd toes
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14
Q

Trisomy 18 - Edward’s syndrome (Meiotic errors)

A

-Head: microcephaly; low set ears; micrognathia; ears low set; cleft lip and palate

-Hands & feet: Clenched hands, overlapping fingers; Rockerbottom feet
Low birth weight
Short sternum
Severe mental retardation

-Organ Malformations:
Umbilical or inguinal hernia

Congenital heart disease (90%)

Congenital kidney abnormalities

Eye abnormalities eg. cataracts, micropthalmia

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15
Q

Trisomy 13- Patau’s syndrome (Meiotic errors)

A

Small at birth
Mental retardation severe
Microcephaly/ sloping forehead
Defects of brain - holoprosencephaly

-Phenotype:
Eyes – microphthalmia, coloboma, retinal dysplasia, palpebral fissures slanted

Cleft lip and/or palate

Ears abnormal and low

Polydactyly & fingers flexed

Heart defect

Abnormal genitalia

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16
Q

Link between Autosomal aneuploidy & maternal age (Meiotic errors)

A
  1. Unfavourable chiasmata distribution (foetus)
  2. Age-dependent deterioration of meiotic structures (10-40y later) - hormonal imbalance, irradiation, oral contraceptives, alcohol, etc
17
Q

Sex chromosome aneuploidy (Meiotic errors)

A

no age-related risk
phenotype less severe than autosomal
sexual orientation not affected

Turner’s syndrome (45,X) - 1/2500

Klinefelter’s syndrome (47,XXY) - 1/1000

47,XYY - 1/1000

47,XXX - 1/1000

18
Q

Features of Turner’s syndrome (Meiotic errors)

A

45, X

-Reproductive
Loss of ovarian function
No puberty
Infertility

-Lymphatic (obstruction)
Webbed neck
Swelling of hands &/or feet

-Others
Skeletal Abnormalities – short stature
Coarctation of aorta
IQ generally normal/reduced compared to sibs

19
Q

Features of Klinefelter syndrome (Meiotic errors)

A

47, XXY
Identified through infertility &/or hypogonadism

-Infertility
May lack secondary sexual characteristics
Testicular dysgenesis
30-50% gynaecomastia (20x risk breast cancer)

-Growth 
Normal in infants, then accelerates
Adults long legs and arms
-IQ normal
Family background IQ important
IQ may decrease with increased Xs
20
Q
  1. Errors at fertilisation
A
  1. Polyploidy (usually triploidy)

2. Molar pregnancy (double paternal, no maternal)

21
Q

Triploidy (Errors at fertilisation)

A

69,XXY or 69,XYY or 69,XXX

2% all pregnancies

99.9% spontaneously abort

1/57000 livebirths

22
Q

Origin of triploidy (Errors at fertilisation)

A

sperm 1N + Egg 2N = Digyny

sperm 2N + Egg N= Diplospermy

2 Sperm Ns + Egg N = Dispermy

23
Q

Parental origin of triploidy (Errors at fertilisation)

A

Double paternal = large placenta
= some growth delay

Double maternal = tiny placenta
= significant growth delay
= head-saving macrocephaly

Conclusions: Maternal genome for foetus
Paternal genome for placenta

24
Q

Molar pregnancy (Errors at fertilisation)

A

Consequences:
Double paternal genome
“Conceptus without an embryo”
Massive cystic placenta

25
Q
  1. Errors at early cleavage
A

(mosaicism = mitotic non-disjunction)

26
Q

Consequences of Mosaicism (Errors at early cleavage)

A

Variable phenotype

Variable lethality foetal vs extraembryonic

Non-identical twin

Tissue-specificity – lateral asymmetry

May generate Uniparental disomy (UPD)

Recurrence risk (if gonadal)

“All females are mosaic”

27
Q

Summary of numerical abnormality

A

Numerical abnormalities frequent (genetically unfit)

Gain or loss of single chromosome (meiosis)

Gain of whole chromosome sets (fertilisation)

Gain or loss during mitosis (post-fertilisation)

28
Q

Chromosome rearrangement - 1) Balanced rearrangements

A

1) Translocation
- Reciprocal
- Robertsonian

2) Inversion
- Pericentric
- Paracentric

3) Insertion

29
Q

Reciprocal translocation

A

Both bits exchange on chromosomes (7 –> 9)

30
Q

Robertsonian translocation

A

A whole arm fusion from a chromosome on another
(13–>15)

acrocentrics
1/1000
no phenotype risk
reproductive risk

31
Q

Inversions (translocation)

A

two types

1) Pericentric
- inverts on both sides of centromere

2) Paracentric
- Inverts in one of the arms of the chromosomes

32
Q

Unbalanced rearrangements

A

Contiguous gene syndromes or genomic disorders
1/2000

Copy number variation (CNV) - Overall net cytogenetic gain &/or loss (from 100s Kb to Mbs)
Commonest = deletions & duplications
Several genes
Mostly sporadic

33
Q

Deletions (interstitial) (Unbalanced rearrangements)

A

A segment within the chromosome is lost

34
Q

Terminal deletion (Unbalanced rearrangements)

A

A whole segment at the end of chromosome is lost

35
Q

Duplications (Unbalanced rearrangements)

A

Gain of segment

gain of two segments can be integrated into chromosome via being directed or inverted

36
Q

Deletions & duplications

A

Phenotype - abnormal gene dosage (several genes)

Variable clinical expression – variable size of imbalance, other genetic and environmental effects

Reciprocal duplications – frequency = deletions

Loss > deleterious than excess

37
Q

Ring chromosome

A

Breakage at either of chromosome and then circularisation of chromosome (basically looks like a plasmid)

38
Q

Summary

A
  1. Structural rearrangements common
  2. Balanced - 5-10% risk gene disruption
    (phenotype)
    - most no phenotypic effect
    - reproductive problems
  3. Unbalanced - phenotype

EMS- gim (11 decks)

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