Chromosome Abnormalities and Genomic Rearrangements Flashcards
Definition of aneuploidy
Wrong no of chromosomes
Definition of cytogenetics
Study of chromosomes (no, structure, deletions, duplications, instability)
Definition of non disjunction
Failure of sister chromatids/homologous chromosomes to separate during cell division
Definition of disomic
1+ chromosome doubled without having the whole genome doubled
Definition of nullsomic
1+ chromosome missing in isolation
Definition of anaphase lag
Chromosome/chromatid does not properly migrate during anaphase and daughter cells lose some genetic info
Definition of germ cell
Embryonic cell with the potential of developing into a gamete
Definition of trisomy rescue
1 copy of 3 chromosome copies lost => normal diploid chromosome
What is cytogenetics
What 5 factors are studied in particular
Study of chromosomes
- no
- structure
- deletions
- duplication
- instability
What are the 3 main types of chromosome abnormalities
Chromosome rearrangements
Whole chromosome aneuploidy
Copy number imbalance
What are the techniques used to investigate chromosomes
- 3 traditional cytogenetic techniques
- 3 molecular cytogenetic techniques
Traditional cytogenetics -G banding -FISH -Breakage Cell culture needed to collect metaphase cells
Molecular cytogenetics -QF-PCR -MLPA -Array CGH Tests done on DNA
What is whole chromosome aneuploidy
What does it cause
What 3 chromosomes are less affected and why
Arises from non disjunction at mitosis/meiosis
Large genomic imbalance => loss of pregnancy unless affected chromosome is gene poor (13, 18, 21)
What are the 2 outcomes of non disjunction in meiosis
2 disomic daughter cells
2 nullsomic daughter cells
Describe the effects of whole chromosome aneuploidy on the zygote
Disomic + Normal?
Nullsomic + Normal?
Disomic + Nullsomic?
Disomic + Normal => Trisomic conceptus
Nullsomic + Normal => Monosomic conceptus
Disomic + Nullsomic => Uniparental disomy
Describe mosaicism
What can happen when a 47 +21 undergoes mosaicism and why
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
What are the 3 locations of mosaicism and their properties
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
What are the 4 types of chromosome rearrangements
Robertsonian translocation
Reciprocal translocation
Inversion
Intrachromosomal insertions
What are Robertsonian translocations
- What are the most common Robertsonian translocations
- What are the consequenes of balanced carriers
- What is the prevalence
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
What are the 2 types of Robertsonian translocation in meiosis
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
What are reciprocal translocations
- what are the consequences of balanced carriers
- what are the most common reciprocal translocations
- what is the prevalence
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
What are the 3 types of reciprocal translocation in meiosis
- types of carrier
- amount of genetic material
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
What are the 2 types of chromosome inversions
Pericentric inversion
-inversion that involves centromere
Paracentric inversion
-inversion that doesnt involve centromere
What is the function of G banding
Can see whether large sections are missing by comparing lengths of chromosomes
Describe the process of FISH
What are the 3 uses
Denatured target DNA + denatured DNA probe with fluorescent marker => target DNA marked with fluorescent marker
- subtelomere probes
- mbanding
- whole chromosome paints
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
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
Describe the potential outcomes of segmental copy number imbalance
Small segments of the genome are repeated
- deletions of repeats
- duplications/triplications
What are microdeletion syndromes
How are they recognizable as syndromes
How does microdeletion arise
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
Describe the method of array CGH
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
How would you interpret the results of an array CGH
- red
- yellow
- green
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
What are the 4 uses of array CGH
Whole chromosome aneuploidy
Microdeletion/duplication syndromes
Subtelomere imbalance
Other regions of imbalance
Describe the variation found between humans in CNV
We normally have many small CNV
Different CNV combinations => phenotypic variation between individuals
Many gene imbalances have unknown functions
How would you ascertain the clinical consequences of a previously unreported imbalance
Inheritance
- de novo => pathogenic
- from affected parent => pathogenic
- healthy parent => benign
No of genes
Specific gene content
What are the issues with accidentally finding pathogenic imbalances
Raise anxiety in family
Extensive, expensive monitoring
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