Chromosome abnormalities, segregation Flashcards
What is a Robertsonian translocation?
How does a Robertsonian karyotype look?
Fusion of the long arms of two acrocentric chromosomes, short arms are lost
Considered balanced - short arms contain repetitive satellite and ribosomal DNA sequences only
Karyotype shows 45 chromosomes
What are acrocentric chromosomes?
Which chromosomes are acrocentric?
Chromosomes where the centromere is not central, have a very small p arm
13, 14, 15, 21, 22, Y
Name the three common reciprocal translocations
t(11;22)
t(4;8)
t(X;Y)(p22;q11)
What is a derivative chromosome?
The translocation product identified according to which centromere it includes
What is a double segment exchange?
What is a single segment exchange?
Double segment exchange - both translocated segments are substantial size
Single segment exchange - one translocated segment is very small
How does an insertion (insertional translocation) occur?
3 break rearrangement involving 2 chromosomes
1 break in recipient chromosome, 2 breaks in donor
What are the risks of Robertsonian translocations to offspring?
Malsegregation of translocation chromosome can lead to Down syndrome, Patau syndrome etc.)
Increased risk of UPD if malsegregation is corrected by trisomy/monosomy rescue - imprinting disorder if 14 and 15 involved
What are the most common Robertsonian translocations?
der(13q14q) and der(14q21q)
What are inversions?
2 break intrachromosomal structural rearrangement
What are the 2 types of inversion?
Paracentric - breakpoints in the same arm
Pericentric - breakpoint in each arm, includes the centromere
What are the implications of an inversion?
Carriers usually phenotypically normal as it’s a balanced rearrangement
Risk of phenotype from position effect, disruption of a gene or epigenetic effect
Infertility in males due to failure of synapsis
Risk to offspring due to inversion loop at meiosis resulting in crossover and therefore imbalances
Risk of acentric or dicentric chr from paracentric inversion
What is an isochromosome?
Unbalanced rearrangment
‘Mirror image’ chromosome - 2 identical arms of the same chromosome on either side of the centromere
What are the implications of an isochromosome
- Loss of expression of genes on missing arm (e.g. Turner syndrome, SHOX)
- If present as a supernumary, results in tetrasomy for the arm (e.g. i(12p) Pallister-Killian syndrome)
How does a ring chromosome arise?
What are the clinical implications?
Most arise sporadically, involved breakage in both arms with fusion at the breakpoints and loss of distal segments
Variable phenotype, depends on size/content of deleted distal segments
r(20) associated with epilepsy
What happens in alternate segregation?
What does it result in?
The two normal homologues segregate together and the two balanced homologues segregate together
Produce balanced gametes
What happens in adjacent 1 segregation?
What does it result in?
Adjacent non-homologous centromeres segregate together (one of each centromere)
Produces only unbalanced gametes
What happens in adjacent 2 segregation?
What does it result in?
The 2 homologous centromeres segregate together
Produces only unbalanced gametes
What is 3:1 segregation? What are the 2 types?
What do they result in?
3 centromeres to one pole, 1 centromere to the other
Tertiary - 2 normal chromosomes and 1 translocated chr
Interchange - 2 translocated chr and 1 normal
What are the implications of carrying a balanced translocation?
Carriers usually phenotypically normal unless positional effect, gene disruption, imprinting
Risk of recurrent miscarriage/infertility
Risk of abnormal offspring due to malsegregation –> imbalance or UPD
Give 2 examples of diseases involving isochromosomes
Pallister-Killian syndrome - supernumerary i(12p) = tetrasomy
45,X/46,X,i(Xq) = Turner syndrome variant
What are the two types of Robertsonian translocation?
- Non-homologous translocation = two different chr
- Homologous translocation = the same chr
What happens to translocation chromosomes during meiosis I?
Form a quadrivalent
In order to match homologous segments they form a pachytene cross
Chromosomes then distributed to poles of the cell
What is the implication of the t(11;22) balanced translocation on offspring?
Carriers phenotypically normal
Prone to 3:1 segregation - one gamete has tertiary trisomy for normal 11, normal 22 + der(22)t(11;22)
If fertilised, results in zygote with 2x normal 11s, 2 normal 22s + der(22)t(11;22) = Emmanuel syndrome
What causes a terminal deletion and what mechanisms can occur to stabilise the chromosome?
Caused by DSBs
- Synthesis of new telomore
- Telomere capture from another chr
- Chr circularisation –> ring chr
What is the phenotype of Emmanuel syndrome?
Pre- & postnatal growth deficiency, microcephaly, hypotonia, severe developmental delay, cleft palate, congenital heart defects, kidney abnormalities
What is the phenotype of Pallister-Killian syndrome?
Multiple congenital anomalies, seizures, severe developmental delay, macrosomia at birth, deafness, distinct dysmorphic features
Give an example of a balanced rearrangement impacting imprinting
Maternal t(7;16) associated with maternal heterodisomy (mat UPD) due to 3:1 segregation and trisomy rescue –> RSS
