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MBOD week 11 > Microdeletions > Flashcards

Microdeletions Flashcards

1
Q

T or F: in each microdeletion syndrome the imbalance affects the same region of the genome from patient to patient.

A

True, while there may be some variability, these are defined as syndromes because the imbalance arises in the same place again and again

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2
Q

What is the critical region?

A
  • region that is affected leading to particular symdrome
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3
Q

What is the lower limit for detection of a genomic imbalance using a karyotype?

A

5 Mb

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4
Q

T or F: microdeletions can cause partial monosomy.

A

True

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5
Q

What is the most susceptible area to microdeletions?

A

the ends of chromosomes

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6
Q

Do microdeletions post a risk to viability?

A

No they generally will be viable

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7
Q

T or F: microdeletions may have relatively mild phenotype and may go completely undetected

A

True

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8
Q

What is a common thread throughout most microdeletion phenotypes?

A

They all share some degree of developmental delay and intellectual disability

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9
Q

Why are intellecutal disabilities always mentioned as characteristics of chromosome abnormality?

A

The brain is a complex organ and requires the proper function of many genes for normal functioning

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10
Q

What causes Prader-Willi Syndrome?

A
  • Microdeletion syndrome with partial monosomy for proximal segment of 15q
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11
Q

What are the signs a child could have Prader-Willi syndrome?

A
  • Hypotonia, feeding difficulties, poor growth, developmental delay, obesity
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12
Q

What is the critical region for Prader-Willi syndrome?

A
  • microdeletion of 15q12 or 15q11-13
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13
Q

What are the common breakpoints in Prader-Willi syndrome?

A
  • BP1, BP2, and BP3
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14
Q

What is type I break in Prader-Willi syndrome?

A
  • BP1-BP3
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15
Q

What is a type II break in Prader-Willi syndrome?

A
  • BP2-BP3
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16
Q

T or F: patients with Type I and II breaks in Prader-Willi syndrome have significantly different phenotypes.

A

False

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17
Q

What are Low Copy Repeats (LCRs) and why do they cause unequal crossing over?

A
  • DNA segments ~200,000 base pairs long the exists in multiple copies
  • It causes misalignment during crossing over and the wrong genes are exchanged so 2 or the same gene can end up on 1 chromosome and one chromosome now lacks it completely
  • when either of these combine with a normal chromosome they will cause partial monosomy
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18
Q

What are symptoms of 22q11.2?

A
  • Cardiac abnormalities (tetralogy of fallot, VSDs)
  • cleft palate
  • Learning difficulties
  • Immune deficiency
  • Hypocalecemia
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19
Q

T of F: two patients with the same 22q11.2 could have quite different manifestations of the disease.

A

True

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20
Q

What two segments often undergo aberrant recombination in 22q11 deletion syndrome?

A

A and D meaning everything between was lost including TBX 1

Note: TBX 1 is believed to contribute to the observed cardiac defects

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21
Q

Are low copy repeats part of the normal genome?

A

Yes, they are abundant and dispersed through out the genome

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22
Q

T or F: microdeletion syndromes are pathogenic CNVs

A

True

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23
Q

Why might you do a prenatal screening for chromosomal abnormalities?

A
  1. May want to do it even for a healthy pregnancy

2. Seeking diagnosis in an abnormal pregnancy

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24
Q

Why might you do a chromosomal analysis on a pediatric patient?

A
  1. Congenital Anomalies
  2. Developemental problems in Childhood
  3. Delayed or abnormal developement of secondary sex characteristics
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25
Q

Why might you do chromosomal analysis on an adult patient?

A
  1. Infertility (failure to concieve or multiple miscarriage

2. Birth of a child with a chromosomal abnormaility

26
Q

What is the difference between diagnostic testing and screening?

A
  • Screening is a low risk clinical encounter (e.g. checking blood pressure, heelstick in newborns)
  • Testing typically uses a gold standard test to establish a diagnosis
27
Q

Is screening a means for a definitive diagnosis?

A

NO - if abnormalities are suspected in screening then a gold standard test should be used to determine a specific diagnosis

28
Q

What is the preferred method of TESTING in adults? what about fetuses?

A

Adults - blood is typically used

Fetuses - aminocentesis and chorionic vilus sampling

29
Q

Is karyotyping considered a “gold standard” test sufficient for diagnosis?

A

Yes

Note: this is the original, low resolution, genetic test - G-banding is the standard preparation

30
Q

What can be detected with a karyotype?

A

aneuploidy

31
Q

When might you want to used a karyotype?

A
  1. Cases of suspected chromosome abnormality (patient presents with Down of Klinefelters)
  2. Suspicion of Balanced rearrangement (couple who has has multiple miscarriages)
  3. Invasive procedure for prenatal diagnosis (e.g. old moms)
32
Q

What are the strengths of karyotyping?

A
  • Widely available
  • scans entire genome
  • best option for balanced structural abnormalities
33
Q

What are the weaknesses of karyotyping?

A
  • Limited resolution (smaller than a few Mb can’t be seen)
  • Slow turnaround time since culture is required
  • Labor intensive; less amenable to high-throughput automation
34
Q

What is FISH?

A
  • Fluorescence in situ Hyrbridizaiton
  • A probe of known sequence and specificity is hybridized to genetic material from a patient
  • Probe is fluorescent so each site of hybridization can be seen
35
Q

T or F: in a karyotype the preparation is taken such that each chromosome seen consists of a replicated chromosome attached at the centromere

A

True

36
Q

What does FISH tell you?

A

if a specific sequence exists in the genome

37
Q

What principle does FISH rely on?

A

Complementary base pairing

38
Q

If you had a normal cell and you tagged a spot on chromosome 21, how many dots would you expect to count? What about in a child with Down syndrome?

A

2 - one on each homologous chromosome

3 dots in a child with downs

39
Q

Is FISH applicable to uncondensed interphase nuclei?

A

Yes, you’ll still see 3 separate dots

40
Q

Is FISH able to identify microdeletions?

A

Yes

  • You can used 2 markers
    (1) one marker is used to identify the chromosome of interest
    (2) a second marker binds to the critical region on that chromosome
  • You should see 2 dots on the critical region of each chromosome (4 dots total) for normal
41
Q

What is Williams Syndrome? Could FISH be used to give a definitive diagnosis?

A
  • Partial monomosomy 7q
  • Mild to moderate intellecutal disability, Cardiac abnormality (aortic stenosis), Distinctive facial appearance
  • Yes, the critical region will be missing on chromosome 7 in affected individuals
42
Q

Can FISH be used to screen for aneuploidy? If so what type of probe is used?

A

Yes a centromere probe is used

43
Q

What are the strengths and weaknesses of FISH?

A

Strengths - results are specific, easy to interpret and versatile in many clinical applications

Weaknesses - you have to know what you’re testing for to select the correct probe, otherwise you may miss the abnormality in testing

44
Q

T or F: both invasive and non-invasive prenatal procedures can be used for diagnostic purposes

A

False, non-invasive procedures can only be used for screening purposes

45
Q

What is the gold standard for prenatal diagnosis of aneuploidy?

A

the use of invasive procedures such as Aminocentesis and CVS to get a karyotype

46
Q

What are the two invasive (diagnostic procedures) for prenatal diagnosis?

A
  1. Amniocentesis - drawing amniotic fluid from the uterus early in the 2nd trimester
  2. Chorionic Villus Sampling (CVS) - chorionic villi taken from placenta in late first trimester
47
Q

What is done with samples obtained via CVS and aminocentesis?

A

Karyotyping

48
Q

What are two non-invasive procedures for SCREENING for chromosome abnormalities?

A
  1. Serum Screening and ultrasound

2. Non-Invasive Prenatal Testing (NIPT) - DNA gathered from maternal circulation

49
Q

T or F: the majority of Down syndrome infants are born to younger mothers

A

True - moms under 35 account for 35%, this is just because the majority of births are by young women even though risk for old women is higher

50
Q

How much fetal cell-free DNA is present in maternal blood and how is this DNA differentiated from maternal DNA?

A
  • 10% of cell-free DNA is fetal

- Tests look for paternal DNA fragments to identify fetal DNA

51
Q

What does NIPT typically test for?

A

Trisomy 21, 18, 13, and sex chromosome aneuploidies

52
Q

How pregnant does the girl have to be to run NIPT?

A

> 10 weeks

53
Q

Suppose you run NIPT and trisomy 21 is indicated, what do you do next?

A
  • Since NIPT is only a screening test you must do an invasive procedure to give a diagnosis
54
Q

What are the strengths of NIPT?

A
  • Noninvasive

- Highly Predictive

55
Q

What are the weaknesses of NIPT?

A
  • many outside targets are misses

- it still requires conformation via invasive methods

56
Q

How does CMA analysis work and what is indicated by each color on the microarray?

A
  • It uses the typical silica chip and DNA regions to match up genes
  • Yellow indicates genes matched up well
  • Red indicates genes missing (partial monosomy)
  • Green indicates extra genes (partial trisomy)
57
Q

What is the lower threshold of base pair abnormalities that can be detected in using CMA?

A

0.5 Mb - it can detect smaller changes but these are mostly just CNVs

58
Q

Is CMA able to differentiate between Robersonian trisomy 21 and regular trisomy 21?

A

No, the actual chromosome is not present, only the genes. Nevertheless, trisomy 21 would be detected using CMA

59
Q

When is CMA recommended?

A
  • Recommended as diagnostic test for individuals with developmental disabilities or congenital anomalies
  • Recommended after fetal anomalies have been detected on ultrasound
60
Q

What are the strengths of CMA?

A
  • Scans entire Genome

- High sensitivity and precise description of abnormality

61
Q

What are the weaknesses of CMA?

A
  • CNVs complicate things (are they benign or pathogenic)
  • Cannot detect balanced rearrangments or point mutations
  • Poor at detecting polyploidy

MBOD week 11 (11 decks)

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