T2: Chromosomal Pathology

Question 1

How do chromosomal changes produce an abnormal phenotype?

Answer 1

• Dosage effect (copy number variation, CNV)
• Loss is usually worse than gain
• Disruption of a gene at a breakpoint
• Position effect - gene in a new chromosomal environment functions inappropriately
Unmasking of a recessive disorder - a deletion on one chromosomal homologue sits opposite a recessive gene leading to the recurrence of a recessive disease where the individual is heterogenous

Question 2

What are types of CNV?

Answer 2

A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next.

• Chromosome number
• Aneuploidy - (euploid = normal)
One or more extra or missing chromosomes. A result of miotic errors usually in oogenesis. There is a strong maternal age effect.
e.g. trisomy, monosomy
• Polyploidy - not associated with a viable outcome. Seen in cancer cells or fatal pregnancy’s. Here we gain whole sets of 23. Chromosome structure
• Deletion
• Duplication
• Mosaicism - different chromosomal makeup in different cells.

Question 3

Give numerical chromosome abnormalities.

Answer 3

This is due to mitotic errors:
- Aneuploidy e.g. Trisomy, Monosomy (not compatible with life)

Trisomies of 13,18 and 21 are viable. All the others are lethal. The genes on these chromosomes are less dosage intolerant than those on the other chromosomes. 18 in particular has few genes than other chromosomes of its size.

Question 4

Give details of Trisomy 21, trisomy 18 and trisomy 13.

Answer 4

Trisomy 13:
 Patau's Syndrome 
- Microcephaly 
- Growth retardation 
- Rocket-bottom feet 
- Clenched hands 
- Cardiac anomalies 
- 1/5000

Trisomy 18: 
Edward's Syndrome
-  Microcephaly 
- Holoprosencephaly 
- Clefting 
- Polydectyly
- 1/5000

Trisomy 21: 
Down's syndrome
- Heart malformations 
- Learning difficulties 
- Gut atresia 
- early dementia 
- Leukemia 
- 1/700

Question 5

Why is sex chromosome aneuploidy phenotype less severe?

Answer 5

This is due to dosage compensation. In women one X chromosome is turned off. Sexual characterise usually remain normal despite how many X chromosomes you have. Many of these disorders are diagnosed late e.g. in male infertility of Klinefelter.

Question 6

What is the parental origin effect in triploidy?

Answer 6

They are surprisingly common early in pregnancy but very few make it to term. The extra chromosomes can be paternal or maternal in origin. If maternal in origin you get grown retardation in the foetus and the placenta (also physical abnormalities in the foetus). However if the extra set is paternal in origin, there is excess growth of the placenta at the expense of normal development of the foetus. This parent of origin effects reflect the fact maternal and paternal chromosomes do not work in the same way (chromosome imprinting).

Question 7

How can we analyse chromosomes?

Answer 7

Cytogenetic (metaphase chromosome) methods:

• G-branding
• FISH

DNA-based methods:

• Chromosome microarray e.g. array CGH
• QR-PCR
• Whole genome sequencing (WGS)

Question 8

What is pericentric and paracentric inversion?

Answer 8

This is to do with the break point on the inversion.

Pericentric - break points are on different arms
Paracentric - the inversion does not involve the centromere
Have different miotic origins and so different outcomes.

Question 9

What is reciprocal translocation?

Answer 9

Reciprocal translocations occur when part of one chromosome is exchanged with another. Translocations occur when chromosomes become broken during meiosis and the resulting fragment becomes joined to another chromosome. Reciprocal translocations are found in approximately 3% of couples with recurrent miscarriage. There may be no imbalance and so it is found in 1/500 normal individual, thee is however a risk to the offspring. There’s an abnormality risk, where the break is at the junction of an important gene. this risk is at 5-10%.

Question 10

What is Robertsonian translocation?

Answer 10

Robertsonian translocation: This is not an exchange of genetic material but a whole arm fusion - acrocentric chromosomes. 1/1000 people carry this. They would have no phenotype but reproductive risk. They have very short arms (acrocentric chromosomes) that have no unique genes - they are made up of repeat sequences, tandem repeats of rDNA and satellite repeats. This is why when fusion occurs, there is no loss of important material. Th acrocentric chromosomes are 13,14,15, 21 and 22.