Chromosomal Abnormalities

Question 1

Why is chromatin important?

Answer 1

Compactness
Affects regulation
3D genome is important

Question 2

What is an ideogram?

Answer 2

Diagram showing chromosome banding

Giesma staining leaves recognisable patterns

Question 3

What is the normal karyotype?

Answer 3

46 XX

46 XY

Question 4

Under what circumstances can expression occur?

Answer 4

Can be tissue specific
Can be at a specific time in development
Can be in response to an event

Question 5

What is the purpose of mitosis?

Answer 5

Two identical daughter cells
Growth and repair
Replace exhausted cells

Question 6

How do you obtain a karyotype?

Answer 6

Obtain blood
Add phytohemagglutinin 
Culture 48-72 hours 
Add colcemid ( arrests cells in metaphase)
Culture briefly
Add KCL to swell cell
Brief digestion with trypsin 
Stain with geisma

Question 7

What is the purpose of meiosis?

Answer 7

Reduction from diploid to haploid
Ensure genetic variation in gametes
Enables random assortment of homologues and recombination

Question 8

What is non-disjunction?

Answer 8

Both chromosomes have gone to one daughter cell at meiosis I
After meiosis II and fertilisation, 2 zygotes have trisomy and 2 monosomy

Can occur at meiosis II
2 normal zygotes
1 trisomy
1 monosomy

Question 9

Why is female meiosis vulnerable?

Answer 9

Paused in utero until puberty
One primary oocyte yields one ovum
Finite number of oocytes

Question 10

What does female non-disjunction cause?

Answer 10

Aneuploidy
Due to degradation of factors which hold homologous chromosomes together
First trimester risk for trisomy
Risk increases with age

Question 11

What does trisomy at chromosome 21 cause?

Answer 11

Down syndrome

Question 12

From what do most trisomy 21 arise?

Answer 12

Maternal non-disjunction

Question 13

What is quantitative fluorescence PCR used for?

Answer 13

Pre-natal screening for trisomy

Question 14

What are the main features of meiotic non-disjunction?

Answer 14

Trisomy for all chromosomes has been detected prenatally
Not all trisomies are compatible with life
Monosomy is poorly tolerated

Question 15

Why is sex chromosome imbalance tolerated?

Answer 15

X-inactivation of excess X chromosomes

Low gene content of Y chromosome

Question 16

What is reciprocal chromosomal abnormalities?

Answer 16

Segment gets swapped between non-homologous chromosomes
Doesn’t often affect phenotype
Can increase risk of miscarriage

Question 17

Why do reciprocal chromosomal abnormalities present a reproductive risk?

Answer 17

Chromosome have to contort into unusual figurations to achieve synapsis at mitosis and meiosis
Increased chance of unbalanced gametes

Question 18

What is the severity of the phenotype dependent on?

Answer 18

Size of imbalance

Gene content

Question 19

How may unbalanced chromosomal abnormalities arise?

Answer 19

De novo
Reciprocal parental abnormality 
Terminal deletion 
Interstitial deletion 
Inversion
Duplication
Ring chromosome

Question 20

What is the phenotype first approach?

Answer 20

Clinical approach to grouping children with similar development delay and/or dysmorphism
Then look for common genetic abnormalities

Question 21

What are the main features of Williams syndrome?

Answer 21

Long philtrum
short, upturned nose
Arched eyebrows
Supravalvular aortic stenosis
Absence of social anxiety

Question 22

What is aCGH?

Answer 22

Array comparative genome hybridisation

Used in preference to karyotyping

Question 23

What are the main features of contiguous gene deletion/duplication syndromes?

Answer 23

Have common breakpoints
Mediated by low copy repeats
Risk of non-allelic homologous recombination may be increased by parental LCR inversions

Question 24

What is the difference between duplication and deletion syndromes?

Answer 24

Duplications usually have a milder phenotype that the reciprocal deletion

Question 25

What is NGS?

Answer 25

Next generation sequencing
Can find abnormalities
Align and compare to reference genome

Question 26

What are indels?

Answer 26

Small point mutations: insertion and deletion

Can completely ablate of alter the function of a gene

Question 27

Why can male meiosis be vulnerable?

Answer 27

No equivalent to menopausal limit

Primary spermatocytes undergo 23 mitotic divisions a year and potentially accumulates defect

Question 28

What effects can paternal age have?

Answer 28

Subset of single gene disorders
Apert syndrome
Crouzon syndrome
Pfeiffer syndrome