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Flora Ross > Mechanisms of chr rearrangements > Flashcards

Mechanisms of chr rearrangements Flashcards

1
Q

How much of the genome do LCRs represent?

A

5-10%, dispersed throughout

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2
Q

What is the major mechanism for CNV generation?

A

Non allelic homologous recombination

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3
Q

Describe NAHR

A

Erroneous pairing and alignment of homologous but non-allelic LCRs. Mediate crossover recombination

Can occur in meiosis (germline rearr) and mitosis (somatic CNVs)

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4
Q

Name 4 disease mechanisms due to NAHR

A

Change in copy number of a dosage sensitive gene

Gene disruption

Fusion gene

Position effect e.g. move away from promoter

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5
Q

Why do deletions have more reported phenotypes than reciprocal duplications?

A

Trisomy is more tolerated than monosomy

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6
Q

Define Haploinsufficiency

A

Half amount of gene product is not sufficient to maintain normal gene function

Hemizygous or heterozygous variants in a HI gene = disease

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7
Q

Define variable expressivity and incomplete penetrance

A

Variable expressivity = phenotype expressed differently among individuals with same genotype

Incomplete penetrance = likelihood of a genotype causing a phenotype[=

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8
Q

Name a reciprocal microdeletion/duplication example

A

17p11.2 - PMP22 - 1.4Mb region

Del = HNPP

Dup = CMT1A

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9
Q

Name an interstitial deletion on chromosome 7 (chr location, size & genes)

A

Williams syndrome due to 7q11.23 deletion

90% = 1.5Mb

28 genes including ELN

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10
Q

How many LCRs mediate the 22q11 recurrent region?

A

8 (LCR22 A-H)

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11
Q

Name 3 clinically distinct syndromes associated with the 22q11 region

A

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

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12
Q

What is the main HI gene associated with 22q11.2 deletion? Function?

A

TBX1

Essential TF for embryonic development

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13
Q

5 clinical features of DiGeorge syndrome

A

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

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14
Q

Cause of Miller-Dieker syndrome

A

17p13.3 deletion involving LIS1

= lissencephaly (smooth brain), dev delay, seizures

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15
Q

2 HI genes in WAGR 11p13 del

A

WT1 and PAX6

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16
Q

Syndrome associated with 4pter deletion

3 clinical features

A

Wold-Hirschhorn

Craniofacial abnormalities e.g. Greek warrior helmet face

Dev delay

Hypotonia

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17
Q

Mechanism for 4pter deletions

A

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

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18
Q

Features of Cri-Du-Chat syndrome

A

5pter del

5-40Mb, size correlates with disease severity

Cat like cry, dev delay (due to CTNND2 HI) and microcephaly

19
Q

Name the 3 major mechanisms for chromosome rearrangements

A

NAHR
Non-Homologous End Joining
Fork Stalling Template Switching

20
Q

Describe the main non-replicative non-homologous DNA repair mechanism

A

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

21
Q

Name 2 main complexes for NHEJ

A

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

22
Q

Name the mechanism for chromosome instability in cancer e.g. iamp(21)

A

Breakage-Fusion-Bridge cycle

Cyclic breakage/fusion of chromatids with no telomeres, forming dicentric chr separated in anaphase

23
Q

3 reasons why Fork Stalling occurs

A

Secondary structures

Lesions in DNA template

dNTP shortage

24
Q

How does FoSTeS cause rearrangements?

A

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

25
Q

Most common mechanism formation of Robertsonian translocations

A

Centric fusion for rob(13;14) and rob(14;15)

26
Q

Mechanism for homologous Robertsonian translocations e.g t(21;21)

A

Misdivision at centromere

27
Q

How many dev delay patients have apparently balanced chr rearrangements?

A

0.6%

28
Q

5 mechanisms of an abnormal phenotypes with a balanced karyotype

A

Disruption of gene at breakpoints

Cryptic imbalances

Position effect

Disturbance of imprinting

UPD

29
Q

Give an example of a rearrangement disrupting a gene

A

Oncogenic fusions in mitosis = constitutively active oncogenes

30
Q

What % of apparently balanced rearrangements are actually unbalanced?

A

37%

31
Q

1 example of position effect due to balanced translocation

A

Isolation from enhancer

t(4;17) 17q breakpoint ~900kb upstream of SOX9 = decreased gene expression = campomelic dysplasia

32
Q

1 example of disturbance of imprinting due to balanced translocation

A

Maternal translocations involving 11p15 move an IC away from H19 = increased gene expression = BWS

33
Q

What is the risk of UPD for a Robertsonian translocation involving chr14/15?

A

Rare - 0.5%. Requires trisomy rescue of free chr from other parent

34
Q

Name the 5 possible segregation patterns for a reciprocal translocation

Total no of possible outcomes?

A

2:2

Alternate
Adjacent 1
Adjacent 2

3:1

Tertiary trisomy
Interchange trisomy

n=16

35
Q

Describe Adjacent-1 segregation

A

Non-homologous centromeres segregate together

More likely when translocated segment is shorter than centric segment

36
Q

Describe Adjacent-2 segregation

A

Homologous centromeres segregate together

More likely when centric segment is shorter than translocated segment

37
Q

When is 3:1 segregation more likely?

A

When 1 chromosome is small or the quad is symmetrical

38
Q

What is Haploid Autosomal Length?

% viable for monosomy/trisomy

A

Correlation of quantitative chromatin imbalance with risk of abnormal offspring

<2%/<4%

39
Q

How many segregation outcomes are there for Robertsonian translocations?

A

6 for heterologous

2 for homologous (no normal gametes)

40
Q

State 3 mechanism of origin for constitutional marker chromosomes

A

Numerical error + partial rescue

Unbalanced rearrangement

U-type meiotic exchange (usually acrocentric)

41
Q

State 3 well characterised syndromes associated with a supernumerary marker chr

A

Pallister Killian mosaic +i(12p)

Emanuel syndrome +der(22)t(11;22)

Cat Eye syndrome +inv dup(22)

42
Q

5 clinical features of Emanuel syndrome

A

Congenital abnormalities inv renal/cardiac

Facial asymmetry

Cleft palate

Severe ID

FTT

43
Q

Describe the Cat Eye syndrome marker chr

A

Symmetrical dicentric marker with tetrasomy 22p + varying lengths of 22q, depending on breakpoint

Type 1 = LCR22-A

Flora Ross (12 decks)

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