Structural chromosomal abnormalities

Question 1

What are the different types of structural abnormalities?

Answer 1

• Translocations (reciprocal and robertsonian)
• Deletion
• Duplication

Question 2

Difference between carrier of a balanced vs unbalanced individual?

Answer 2

Person: carrier of a balanced translocation
* Normal intact chromosome 1 & 22
* Derivative chromosomes
* No net gain or loss of genetic material
* Involve any chromosome and any size fragment
* Relatively common; 1 in 930 ppl

Unbalanced individual
* In meiosis (gamete formation), the homologous chromosomes want to pair with their partner in meiosis I
* (Normally form a bivalent structure)

Question 3

Reciprocal vs robertsonian translocation?

Answer 3

Consequences of reciprocal translocations in meiosis
* Get a tetravalent or quadrivalent structure (involves 4 chromosomes)
* Balanced: 2 normal chromosomes + 2 derivatives
* Have to consider; how chromosomes separate at meiosis I & II (to see what will be in the gamete) depends on which line, they separate along
* Upon fertilisation, can cause a problem
* Trisomic and miosmic mixture; Monosomy is the absence of one member of a chromosome pair (2𝑛−1), while trisomy is the presence of an extra chromosome (2𝑛 + 1), both often caused by errors during cell division
* Random distribution for division
* Only when both derivates go into one gamete and two intact go into another gamete = zygote formed will either be normal with intact chromosomes or balanced carrier like parents

Result of unbalanced reciprocal translocation
* Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)
* Learning difficulties, physical disabilities
* Tend to be specific to each individual so exact risks and clinical features vary

Robertsonian translocation
* Two Acrocentric chromosomes join near centromere with the loss of p arms (Sometimes when you get Double stranded breaks: P arms can be chopped off -> rather than being stuck back together -> q arms are stuck together at the central centromere)
* Balanced carrier has 45 chromosomes
* If 46 chromosomes present including robertsonian then must be unbalanced
* P arms encode rRNA (multiple copies so not deleterious to lose one)
* Robertsonian translations 13;14 and 14;21 relatively common. 21;21 translocation leafs to 100% risk of Down syndrome in foetus
* Trisomy 21 due to NDJ (3 copies of chromosome 21)
* Trisomy 21 due to robertsonian translocation (2x copies of 21 and 14 and 21)

Outcomes of translocations
* Very difficult to predict
* Only have approximate probability of producing possible gametes
* Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem
* Some unbalanced outcomes may lead to miscarriage later on and present clinically
* Some may result in live-born baby with various problems

Question 4

What is translocation?

Explain the process of non-homologous end joining

Answer 4

• Translocation: exchange of two segments between non-homologous (not pairs) chromosomes (physical swapping of a chunk of chromosome from one to another)
• Common way it occurs is due to inappropriate non-homologous end joining.
• NHEJ: particular form of DNA repair mechanism; will rejoin broken up chunk of chromosome (to its parent chromosome)
• Sometimes you can have double strand breaks in the DNA’ separating the chromosomes!
• Sometimes the mechanism inappropriately sticks the chromosome onto a different chromosome. (There’s been an exchange of material, e.g. chunk of chromosome 22 broken off gets stuck to the free end of chromosome 1 creating a derivative (mixture of 2 chromosomes -> inappropriate NHEJ)

Question 5

Explain how unequal crossing over can result in deletions and duplications

Answer 5

Deletions
* 1:7000 live births
* May be terminal or interstitial
* Causes a region of monosomy
* Haploinsufficiency of some genes
* Continuous gene syndrome (multiple, unrelated clinical features)
* Phenotype is specific for size and place on deletion
* Gross deletions seen on metaphase spread on G-banded karyotype

Micro deletions
* Many patients had no abnormality visible on metaphase spread
* High resolution banding, FISH and now CGH showed ‘micro’ deletions
* Only a few genes may be lost or gained
* Velocardiofacial (diverge), 22q11
* Wolf-hirschhorn, 4p16
* Williams, 7q11
* Smith-magenis,17p11

Unequal crossing over
* Exchange of genetic material between homologous pairs of chromosomes, but they have not aligned appropriately
* Can get simultaneous deletions and duplications on the individual chromatids that are ultimately found in the gametes