Mechanisms of chr rearrangements Flashcards
How much of the genome do LCRs represent?
5-10%, dispersed throughout
What is the major mechanism for CNV generation?
Non allelic homologous recombination
Describe NAHR
Erroneous pairing and alignment of homologous but non-allelic LCRs. Mediate crossover recombination
Can occur in meiosis (germline rearr) and mitosis (somatic CNVs)
Name 4 disease mechanisms due to NAHR
Change in copy number of a dosage sensitive gene
Gene disruption
Fusion gene
Position effect e.g. move away from promoter
Why do deletions have more reported phenotypes than reciprocal duplications?
Trisomy is more tolerated than monosomy
Define Haploinsufficiency
Half amount of gene product is not sufficient to maintain normal gene function
Hemizygous or heterozygous variants in a HI gene = disease
Define variable expressivity and incomplete penetrance
Variable expressivity = phenotype expressed differently among individuals with same genotype
Incomplete penetrance = likelihood of a genotype causing a phenotype[=
Name a reciprocal microdeletion/duplication example
17p11.2 - PMP22 - 1.4Mb region
Del = HNPP
Dup = CMT1A
Name an interstitial deletion on chromosome 7 (chr location, size & genes)
Williams syndrome due to 7q11.23 deletion
90% = 1.5Mb
28 genes including ELN
How many LCRs mediate the 22q11 recurrent region?
8 (LCR22 A-H)
Name 3 clinically distinct syndromes associated with the 22q11 region
DiGeorge syndrome
~3Mb deletion
LCR22A-D
Emanuel syndrome
+der(22)t(11;22)(q23.3;q11.2)
Breakpoint in LCR22B
Cat Eye syndrome
+inv dup(22)
Variable breakpoints
What is the main HI gene associated with 22q11.2 deletion? Function?
TBX1
Essential TF for embryonic development
5 clinical features of DiGeorge syndrome
Cardiac defects
Thymic hypoplasia (require irradiated blood for cardiac surgery so important to exclude DiG if in differential, & avoid live vaccines)
Cleft palate
Hypocalcaemia (vitD supplement)
LD
Cause of Miller-Dieker syndrome
17p13.3 deletion involving LIS1
= lissencephaly (smooth brain), dev delay, seizures
2 HI genes in WAGR 11p13 del
WT1 and PAX6
Syndrome associated with 4pter deletion
3 clinical features
Wold-Hirschhorn
Craniofacial abnormalities e.g. Greek warrior helmet face
Dev delay
Hypotonia
Mechanism for 4pter deletions
45% (de novo or inherited) = unbalanced t(4;8)(p16;p23), a recurrent translocation occurring due to NAHR between olfactory receptor gene clusters on chr4/8
Features of Cri-Du-Chat syndrome
5pter del
5-40Mb, size correlates with disease severity
Cat like cry, dev delay (due to CTNND2 HI) and microcephaly
Name the 3 major mechanisms for chromosome rearrangements
NAHR
Non-Homologous End Joining
Fork Stalling Template Switching
Describe the main non-replicative non-homologous DNA repair mechanism
Non-Homologous End Joining
Ligation of 2 DSBs with no homology
Usually results in small insertions or deletions (1-4bp) due to editing to make ends compatible for joining
Name 2 main complexes for NHEJ
Heterodimer Ku70:Ku80 recognises DSBs and form scaffold to hold ends together
Artemis complex for exo/endo nuclease preparation of the DNA ends for joining
Name the mechanism for chromosome instability in cancer e.g. iamp(21)
Breakage-Fusion-Bridge cycle
Cyclic breakage/fusion of chromatids with no telomeres, forming dicentric chr separated in anaphase
3 reasons why Fork Stalling occurs
Secondary structures
Lesions in DNA template
dNTP shortage
How does FoSTeS cause rearrangements?
3’ lagging strand of a stalled replication fork anneals to a nearby (spatial) replication fork ssDNA strand due to microhomology
Rearrangement depends on relative position of two forks
e.g. switch to downstream = deletion by forward invasion
e.g. inversions originate depending on whether lagging or leading strand is invaded and the direction of fork progression
Most common mechanism formation of Robertsonian translocations
Centric fusion for rob(13;14) and rob(14;15)
Mechanism for homologous Robertsonian translocations e.g t(21;21)
Misdivision at centromere
How many dev delay patients have apparently balanced chr rearrangements?
0.6%
5 mechanisms of an abnormal phenotypes with a balanced karyotype
Disruption of gene at breakpoints
Cryptic imbalances
Position effect
Disturbance of imprinting
UPD
Give an example of a rearrangement disrupting a gene
Oncogenic fusions in mitosis = constitutively active oncogenes
What % of apparently balanced rearrangements are actually unbalanced?
37%
1 example of position effect due to balanced translocation
Isolation from enhancer
t(4;17) 17q breakpoint ~900kb upstream of SOX9 = decreased gene expression = campomelic dysplasia
1 example of disturbance of imprinting due to balanced translocation
Maternal translocations involving 11p15 move an IC away from H19 = increased gene expression = BWS
What is the risk of UPD for a Robertsonian translocation involving chr14/15?
Rare - 0.5%. Requires trisomy rescue of free chr from other parent
Name the 5 possible segregation patterns for a reciprocal translocation
Total no of possible outcomes?
2:2
Alternate
Adjacent 1
Adjacent 2
3:1
Tertiary trisomy
Interchange trisomy
n=16
Describe Adjacent-1 segregation
Non-homologous centromeres segregate together
More likely when translocated segment is shorter than centric segment
Describe Adjacent-2 segregation
Homologous centromeres segregate together
More likely when centric segment is shorter than translocated segment
When is 3:1 segregation more likely?
When 1 chromosome is small or the quad is symmetrical
What is Haploid Autosomal Length?
% viable for monosomy/trisomy
Correlation of quantitative chromatin imbalance with risk of abnormal offspring
<2%/<4%
How many segregation outcomes are there for Robertsonian translocations?
6 for heterologous
2 for homologous (no normal gametes)
State 3 mechanism of origin for constitutional marker chromosomes
Numerical error + partial rescue
Unbalanced rearrangement
U-type meiotic exchange (usually acrocentric)
State 3 well characterised syndromes associated with a supernumerary marker chr
Pallister Killian mosaic +i(12p)
Emanuel syndrome +der(22)t(11;22)
Cat Eye syndrome +inv dup(22)
5 clinical features of Emanuel syndrome
Congenital abnormalities inv renal/cardiac
Facial asymmetry
Cleft palate
Severe ID
FTT
Describe the Cat Eye syndrome marker chr
Symmetrical dicentric marker with tetrasomy 22p + varying lengths of 22q, depending on breakpoint
Type 1 = LCR22-A
