Chromosomal Abnormalities

Question 1

What is metaphase?

Answer 1

• Chromosomes are condensed and can be karyotyped during metaphase
• Each chromosome comprises two chromatids at this point
• 4n prior to cell division

Question 2

How is DNA compacted?

Answer 2

Chromatin
•Its not just about fitting a lot of DNA into the cell
•Proteins bound to the chromatin affect its regulation
•The 3D genome is important

Question 3

What is G banded architecture?

Answer 3

Ideogram
•Chromosomes have some common structural features
•Giemsa staining leaves a recognizable pattern of bands

Question 4

When is expression?

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

• To create two identical daughter cells
• For growth and repair
• To replace exhausted cells
• 2n to 2n

Question 6

How do you culture and harvest?

Answer 6

1. 0.5ml blood in 5ml culture medium
2. Add phytohemagglutinin (stimulates lymphocytes to divide)
3. Culture 48-72 hours
4. Add colecmins (arrests cells in metaphase)
5. Culture breifly; add hypotonic KCl to swell cells; fix in 3:1 methanol: acetic acid; drop on to microscopic slide
6. Brief digestion with trypsin stain with Giemsa

Question 7

What is the purpose of meiosis?

Answer 7

• To achieve reduction from diploid (2n=46) to haploid (n=23)
• To ensure genetic variation in the gametes
• Enables random assortment of homologues and recombination

Question 8

Why is there vulnerability of female meiosis?

Answer 8

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

Question 9

What is female non-disjunction?

Answer 9

•Most aneuploidy caused by non-disjunction arises in oogenesis
•Likely due to degradation of factors which hold homologous chromatids together
-Risk of maternal non-disjunction increases with age
-First trimester risk for trisomy 13,18 and 21

Question 10

When does most trisomy 21 arise?

Answer 10

Maternal non-disjunction

Question 11

What is Chromosomal aneuploidy?

Answer 11

Meiotic non-disjunction
•Trisomy for all chromosomes has been detected prenatally
•Not all trisomies are compatible with life
•Monosomy is poorly tolerated

Question 12

Why is sex chromosome imbalance tolerated?

Answer 12

• X-inactivation of excess X chromosomes

* Low gene content of Y chromosome

Question 13

What reciprocal chromosomal abnormalities have in common?

Answer 13

• Carriers (1 in 1000) are usually phenotypically normal
• Chromosomes have to contort into unusual figurations to achieve synapsis at mitosis and meiosis
• Present a reproductive risk: increased chance of unbalanced gametes

Question 14

What are unbalanced chromosomal abnormalities?

Answer 14

• Severity of phenotype is dependent on gene content of affected segment
• Trisomy is usually more tolerated than monosomy
• May arise de novo or from a reciprocal parental abnormality

Question 15

Describe Contiguous gene deletion syndromes:

The ‘phenotype first’ approach

Answer 15

• Clinical approach to grouping children with similar developmental delay and/or dysmorphism, then looking for common genetic abnormalities
• Yielded many ‘classical’ contiguous gene deletion syndromes

Question 16

What are the symptoms of of Williams syndrome (7q11.23 deletion)?

Answer 16

• Long philtrum
• Short, upturned nose
• Arched eyebrows
• Supravalvular aortic stenosis
• Friendly, social ‘cocktail party’ personality – an absence of social anxiety

Question 17

What are the phenotypes caused by in Williams syndrome (7q11.23 deletion)?

Answer 17

•Phenotypes caused by imbalance of genes which are unrelated apart from their genomic location

Question 18

What are continuous gene deletion/ duplication syndromes?

Answer 18

• Have common breakpoints
• Mediated by low copy repeats (LCRs)
• Risk of NAHR may be increased by parental LCR inversions

Question 19

What re the symptoms of 7q11.23 duplication syndrome?

Answer 19

•Delayed speech development
•Autistic behaviours that affect social interaction and communication
•Dilatation of the aorta
•Flat eyebrows
•Broad nose and short philtrum
Duplications usually have a milder phenotype than the reciprocal deletion

Question 20

Describe genetic analysis

Answer 20

• Cost of genomic analysis greatly reduced
• Able to detect smaller imbalances
• Increased appetite for a genetic diagnosis