Chromosome Abnormalities and Genomic Rearrangements

Question 1

Definition of aneuploidy

Answer 1

Wrong no of chromosomes

Question 2

Definition of cytogenetics

Answer 2

Study of chromosomes (no, structure, deletions, duplications, instability)

Question 3

Definition of non disjunction

Answer 3

Failure of sister chromatids/homologous chromosomes to separate during cell division

Question 4

Definition of disomic

Answer 4

1+ chromosome doubled without having the whole genome doubled

Question 5

Definition of nullsomic

Answer 5

1+ chromosome missing in isolation

Question 6

Definition of anaphase lag

Answer 6

Chromosome/chromatid does not properly migrate during anaphase and daughter cells lose some genetic info

Question 7

Definition of germ cell

Answer 7

Embryonic cell with the potential of developing into a gamete

Question 8

Definition of trisomy rescue

Answer 8

1 copy of 3 chromosome copies lost => normal diploid chromosome

Question 9

What is cytogenetics

What 5 factors are studied in particular

Answer 9

Study of chromosomes

• no
• structure
• deletions
• duplication
• instability

Question 10

What are the 3 main types of chromosome abnormalities

Answer 10

Chromosome rearrangements
Whole chromosome aneuploidy
Copy number imbalance

Question 11

What are the techniques used to investigate chromosomes

• 3 traditional cytogenetic techniques
• 3 molecular cytogenetic techniques

Answer 11

Traditional cytogenetics
-G banding
-FISH
-Breakage
Cell culture needed to collect metaphase cells

Molecular cytogenetics
-QF-PCR
-MLPA
-Array CGH
Tests done on DNA

Question 12

What is whole chromosome aneuploidy
What does it cause
What 3 chromosomes are less affected and why

Answer 12

Arises from non disjunction at mitosis/meiosis

Large genomic imbalance => loss of pregnancy unless affected chromosome is gene poor (13, 18, 21)

Question 13

What are the 2 outcomes of non disjunction in meiosis

Answer 13

2 disomic daughter cells

2 nullsomic daughter cells

Question 14

Describe the effects of whole chromosome aneuploidy on the zygote

Disomic + Normal?
Nullsomic + Normal?
Disomic + Nullsomic?

Answer 14

Disomic + Normal => Trisomic conceptus

Nullsomic + Normal => Monosomic conceptus

Disomic + Nullsomic => Uniparental disomy

Question 15

Describe mosaicism

What can happen when a 47 +21 undergoes mosaicism and why

Answer 15

Presence of 2+ cell populations with different genotypes in individual who has developed from a single fertilised egg

47 +21 => 47 +21 and 46

Can be due to

• non disjunction
• anaphase lag

Question 16

What are the 3 locations of mosaicism and their properties

Answer 16

Somatic

• results in abnormal phenotypes
• phenotype can be ameliorated by a normal cell line

Gonadal

• during formation of germ cells
• normally only found after 2 pregancies with same ‘de novo abnormality’

CPM (confined placental mosaicism)

• confined to extraembryonic tissue, not always detected
• normal outcome/can compromise placental function/uniparental disomy after trisomy rescue

Question 17

What are the 4 types of chromosome rearrangements

Answer 17

Robertsonian translocation
Reciprocal translocation
Inversion
Intrachromosomal insertions

Question 18

What are Robertsonian translocations

• What are the most common Robertsonian translocations
• What are the consequenes of balanced carriers
• What is the prevalence

Answer 18

Results from fusion of 2 acrocentric chromosomes (13, 14, 15, 21, 22)

Most common (13,14) and (14,21)

Balanced carriers phenotypically normal with reproductive risks

• recurrent miscarriages
• Patau or Downs
• male infertility

Question 19

What are the 2 types of Robertsonian translocation in meiosis

Answer 19

Alternate segregation

• Both acrocentric chromosomes go to 1 daughter cell
• Robertsonian allele isolated in other daughter cell

Adjacent segregation

• Each acrocentric chromosome goes to each daughter cell
• Robertsonian allele passed on with 1 chromosome

Question 20

What are reciprocal translocations

• what are the consequences of balanced carriers
• what are the most common reciprocal translocations
• what is the prevalence

Answer 20

Can be between any segments of any non homologous

Almost always unique to the family

Balanced carriers phenotypically normal with reproductive risks but dependent on size of translocated segments

• infertility
• miscarriage
• child with congenital anomalies

Only 1 recurrent RT : 46XX t(11,22)(q23.3, q11.2)

Prevalence of 1 in 500

Question 21

What are the 3 types of reciprocal translocation in meiosis

• types of carrier
• amount of genetic material

Answer 21

Alternate segregation

• Balanced carriers
• correct amount of genetic material found in each daughter cell

Adjacent segregation

• unbalanced carrier
• each daughter cell has a reciprocal translocated chromosome
• has duplicated section of a chromosome

3: 1 segregation
- unbalanced carrier
- 1 daughter cell has the correct no of 1 chromosome and missing 1 haploid chromosome
- other daughter cell has correct no of 1 chromosome and diploid chromosome

Question 22

What are the 2 types of chromosome inversions

Answer 22

Pericentric inversion
-inversion that involves centromere

Paracentric inversion
-inversion that doesnt involve centromere

Question 23

What is the function of G banding

Answer 23

Can see whether large sections are missing by comparing lengths of chromosomes

Question 24

Describe the process of FISH

What are the 3 uses

Answer 24

Denatured target DNA + denatured DNA probe with fluorescent marker => target DNA marked with fluorescent marker

• subtelomere probes
• mbanding
• whole chromosome paints

Question 25

How would you interpret the ratios from QF-PCR - 2 different chromosomes - 2 homologous and 1 different chromosome (trisomy) - 3 different chromosomes (trisomy) - 2 homologous chromosomes

Answer 25

2 different chromosomes -1:1 => disomy 2 homologous and 1 different chromosome (trisomy) -2:1 => trisomy 3 different chromosomes (trisomy) -1:1:1 => trisomy 2 homologous chromosomes -1:1 OR 1:1:1 => a mystery

Question 26

Describe the potential outcomes of segmental copy number imbalance

Answer 26

Small segments of the genome are repeated - deletions of repeats - duplications/triplications

Question 27

What are microdeletion syndromes How are they recognizable as syndromes How does microdeletion arise

Answer 27

Submicroscopic chromosomal deletions that can't be detected by G banding Recognizable as syndromes due to low frequency of occurence Unequal crossing over within low copy repeat due to genetic structure => 1 chromosome has a microduplication, other has a microdeletion

Question 28

Describe the method of array CGH

Answer 28

Array=many DNA probes attached to a glass slide that can bind to complementary sequences Test DNA and reference DNA marked with different fluorescent markers Oligonucleotide arrays often include 60000 probes

Question 29

How would you interpret the results of an array CGH - red - yellow - green

Answer 29

Red spot -more test material than reference => duplication in patient genome Yellow spot -equal amounts of test and reference => same no of repeats Green spots -more reference material than test => deletion in patient genome

Question 30

What are the 4 uses of array CGH

Answer 30

Whole chromosome aneuploidy Microdeletion/duplication syndromes Subtelomere imbalance Other regions of imbalance

Question 31

Describe the variation found between humans in CNV

Answer 31

We normally have many small CNV Different CNV combinations => phenotypic variation between individuals Many gene imbalances have unknown functions

Question 32

How would you ascertain the clinical consequences of a previously unreported imbalance

Answer 32

Inheritance - de novo => pathogenic - from affected parent => pathogenic - healthy parent => benign No of genes Specific gene content

Question 33

What are the issues with accidentally finding pathogenic imbalances

Answer 33

Raise anxiety in family Extensive, expensive monitoring Don't miss an opportunity to make a difference in someones future