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CMD Block 2 > Microdeletions and Genomic Imbalance > Flashcards

Microdeletions and Genomic Imbalance Flashcards

1
Q

Where are the genes associated with a disease phenotype found?

A

critical region

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2
Q

What happens to the critical region to cause a disease phenotype

A

deletion of multiple adjacent genes

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3
Q

What causes deletion of genes in the critical region?

A

recombination between misaligned repeats

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4
Q

What is caused by abnormalities of 2 or more genes that are located next to each other on a chromosome

A

contiguous gene syndrome (i.e. Prader-Willi Syndrome (interstitial deletion)

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5
Q

What is the inappropriate dosage of critical genes within a discrete genomic segment?

A

segmental aneuploidy syndrome

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6
Q

What are microdeletions?

A

small partial monosomy

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7
Q

What are microduplications?

A

small partial trisomy

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8
Q

What are subtelomeric rearrangements?

A

terminal rearrangements and mostly microdeletions at chromosome ends

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9
Q

What are chromosome deletions (partial monosomies) that may be too small for detection by routine methods (light microscopy) ?

A

microdeletions

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10
Q

Interstitial and terminal deletions ____ Mb cannot be detected reliably.

A

less than 5 Mb

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11
Q

Almost all patients with a microdeletion syndroms exhibit ______ plus syndrome specific anomalies.

A

developmental/intellectual disability

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12
Q

What causes Prader-Willi syndrome?

A

interstitial deletion of q12 on chromosome 15

= imprinting disorder (covered in later lecture)

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13
Q

What are the symptoms of Prader-Willi?

A
  • hypotonia (low muscle tone) in infancy
  • childhood hyperphagia (obesity)
  • metal retardation
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14
Q

What defines the breakpoints on a chromosome that result in the loss of the critical region?

A

presence of low copy repeats that flank the critical region

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15
Q

What occurs at these breakpoints?

A

unequal crossing over of low copy repeats (due to misalignement of low copy repeats on chromosomes)

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16
Q

Crossover in misaligned segments leads to 2 abnormal products…

A

duplication and deletion

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17
Q

When in the cll cycle does this unequal crossing over occur?

A

meiotic pairing of chromosomes (metaphase)

18
Q

____ repeats cause a gene segment to have a flipped orientation between repeats.

A

inverted

19
Q

_____ repeats cause a gene deletion/duplication of the segment between the repeats

A

direct

20
Q

T or F: genomic rearrangement is caused by illegitimate recombination between low copy repeats

A

true

21
Q

T or F: low copy repeats are not abundantly distributed throughout the genome.

A

F: they are abundant (5-10% of genome)

22
Q

What 2 changes can recombination between misaligned repeats cause?

A
  • normal copy number variation (CNV)

- segmental aneuploidy syndromes

23
Q

What are the 3 diagnostic tests used to determine genomic imbalance?

A
  1. std karyotype
  2. FISH
  3. Chromosomal Microarray Analysis (CMA)/Array Comparative Genome Hybridization (aCGH)
24
Q

If you have already identified the disorder and know the gene duplication causing it, what diagnostic test would you perform to confirm your suspicion?

A

FISH

25
Q

Describe how a FISH work?

A

add 2 probes to pt DNA

  1. ID the chromosome of interest (and works as a control)
  2. Test probe that is specific to the deletion you are looking for

if there is only 1 test probe showing up, the Dx is confirmed

26
Q

What genomic imbalance leads to WIllis syndrome?

A

interstitial deletion of q11 on chromosome 7

27
Q

Describe how a comparative genome hybridization by microarray can Dx a genomic imbalance?

A
  • combine pt DNA with control DNA

- apply to microarray and evaluate ratio of patient:control copy numbers

28
Q

What is the ratio of pt:control copy numbers that indicates a normal/balanced genome?

A

1:1

29
Q

What is the ratio of pt:control copy numbers that indicates a genome with a microdeletion?

A

1:2

30
Q

What is the ratio of pt:control copy numbers that indicates a genome with a microduplication?

A

2:1

31
Q

What are the limitations of CMA/aCGH?

A
  1. it cannot detect balanced chromosome rearrangements
  2. it can tell you if there is an imblanance by not the mechanism of the imbalance
  3. does not detect some polyploidies, base pair changes in DNA
32
Q

T or F: A balanced genome will result in a normal CMA

A

true

33
Q

T or F: A normal aCGH can rule out most of the known genetic syndromes

A

False: many genetic changes are not caused my deletions or duplications of chromosome material

34
Q

T or F: aCGH simultanously and rapidly evaluates thousands of regions of the genome

A

true

35
Q

Why would you want to perform an aCGH when a std karyotype was sufficient for Dx?

A

to confirm and further characterize the chromosome imbalance

36
Q

What can you deduce from a FISH assay in which the test probe is identified in 3 places, 2 of which are very close together?

A

there is an interstitial/microdupication of the tested gene segment (=partial trisomy NOT full)

37
Q

What can you deduce from a FISH assay in which the test probe is identified in 3 places, none of which are very close together?

A

There is an extra chromosome (if extra control probe present)
OR possibly a supernumerary chromosome if control probe present but produces a small signal

38
Q

Can a CMA identify the gene segment on a chromosome that is duplicated or deleted?

A

yes; the entire genome is used and ordered so that the exact segment can be identified

39
Q

What is the major adv to CMA over FISH?

A

If you do not have a specific deletion or duplication as the cause of a pt’s phenotype, you can use the CMA to examine the entire genome for imbalances

40
Q

Which test will provide parents with recurrence risk?

A

FISH (or std karyotype)

41
Q

Why are parents tested?

A

to determine if the imbalance is de novo or inherited

-if inherited other family members can be tested for their reproductive risk

42
Q

What is the major disadv to CMA?

A

it cannot detect balanced rearrangements

CMD Block 2 (38 decks)

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