Translocations and Aneuploidies

What specific chromosomes are involved in Robertsonian translocations?

13,14,15,21,22

What characteristics do the chromosomes involved in Robertsonian translocations have in common?

• Acrocentric chromosomes

• Centromere is located near the end of the chromosome

What is a Robertsonian Translocation?

A type of chromosomal rearrangement where two acrocentric chromosomes fuse at their centromeres, resulting in one larger chromosome and the loss of the short arms.

What is the product of a Robertsonian translocation?

• Total of 45 chromosomes instead of 46

• Loss of short arms and fusion of long arms

What are the viable trisomies?

• Trisomy 13

• Trisomy 18

• Trisomy 21

What diseases are associated with trisomy 13?

Patau Syndrome

What diseases are associated with trisomy 18?

Edwards syndrome

What diseases are associated with trisomy 21?

Down syndrome

How are the breakpoints for Robertsonian translocations written using ISCN?

• q10;q10

  • Conventional breakpoints

What technique needs to be performed before writing an ISCN?

Karyotyping

What methods are used to quantify risks of a couple having a live-born child with an unbalanced product of a translocation?

1. HAL (Haploid Autosomal Length)

2. Empiric Risk Calculations

3. Private Risk

How does HAL quantify risks of couples having a live-born child with an unbalanced product of a translocation?

• Provides Yes or No answer

• Calculate fraction of the total autosome length that will be trisomic and monosomic respectively and plot on a graph

How does Empiric Risk quantify risks of couples having a live-born child with an unbalanced product of a translocation?

• Use data in Gardner and Sutherland to find imbalances in the region of interest

• Data tables may not include precise translocation

How does Private Risk quantify risks of couples having a live-born child with an unbalanced product of a translocation?

• If family is large enough

• If other members are carriers of the translocation

• Calculate risk by looking at number of segregations that resulted in normal births vs abnormal births

What advice can be given to a couple unable to conceive when one parent is a balanced translocation carrier?

• Offer PGD (Pre implantation genetics diagnosis)

• Highlight possibility of normal children due to alternate segregation

• Explain child might also be a balanced translocation carrier

  • If there’s a future pregnancy can perform a CVS with FISH karyotyping for rapid results

What is PGD/PGT?

• Preimplantation genetics diagnosis/ Preimplantation genetic testing

• Selecting embryos with normal balanced karyotypes before they are implanted in the womb

• Using IVF

What follow up action should be taken for extended family when a balanced translocation carrier is identified?

• Test parents (if possible, if alive) to understand if translocation is de novo or inherited

• Full family history for extended family with cascade testing

• Find if there’s any history of abnormal children/ miscarriages in family to indicate possibility of abnormal viable offspring

What testing can be performed for couples with recurrent miscarriages?

• Karyotype (any translocations)

• If natural pregnancy occurs = CVS (QF-PCR or FISH) - has risk of miscarriage

  • To see if child will be healthy

• PGD/ PGT

Why are carriers of Robertsonian translocations not affected/ don’t have a phenotype despite a loss of genetic material in the p arms?

• P arms of acrocentric chromosomes are very short

• Contain only rRNA/ NOR regions

• Means same genes are present on all acrocentric chromosomes therefore loss doesn’t cause a phenotype

What is formed when Robertsonian translocation chromosomes pair in prophase I of meiosis?

TRIVALENT

What are the possible segregation patterns for Robertsonian translocations? What zygotes do they produce?

• Alternate = normal or balanced carrier (viable)

• Adjacent = trisomy (possibly viable) / monosomy (inviable)

• 3:0 = double trisomy or double monosomy (inviable)

What should be drawn when asked for gametes?

Just a single persons chromosomes

What should be drawn when asked for zygotes?

2 peoples chromosomes (fertilised)

What is a homologous Robertsonian translocation/ isochromosome formation?

• Robertsonian translocation between the same chromosome e.g. 21:21

• No possibility for normal/ balanced translocation carrier

• Can only be de novo

What are the options for a homologous Robertsonian translocation/ isochromosome in terms of future pregnancy?

• Cannot use PGD as normal/ balanced translocation carrier is not possible

• Sperm donor

• Adoption

How do you calculate the Empiric Risk?

• Find percentages for specific breakpoints on Gardner and Sutherland

  • Using the smallest risk percentage divide by 2

Why would we not use a HAL calculation for aneuploidies in 13,18,21,X and Y?

We know these are viable aneuploidies so there is no need to do a viability calculation

Why would we not do a private risk calculation for a de novo variant?

If it’s de novo then other family members won’t have the variant therefore not possible to perform this kind of risk calculation

Summarise main points a genetic counsellor should cover for a balanced translocation carrier risks to pregnancy (assuming it involves a chromosome with viable trisomy)

• Possible outcomes of pregnancy: healthy/ normal child, affected child (trisomy) or a miscarriage

• Alternate segregation = normal child or balanced translocation carrier

• Adjacent-1 segregation = Trisomic/ monosomic child (monosomies inviable)

• Adjacent-2 segregation = same as Adjacent-1 but larger imbalances

• 3:1/ 4:0 = inviable

• Options: PGD/pgt = healthy child with IVF, CVS after natural pregnancy