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Molecular Diagnostics > Lecture 7: Molecular Detection of Inherited and Metabolic Diseases > Flashcards

Lecture 7: Molecular Detection of Inherited and Metabolic Diseases Flashcards

1
Q

Type of mutations that are inherited from a parent and are present throughout a person’s life in virtually every cell in the body

A

Inherited (germ line)

-These mutations are also called germline mutations because they are present in the parent’s egg or sperm cells, which are also called germ cells.

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2
Q

Type of mutation that occurs at some time during a person’s life
-present in only certain cells, not in every cell in the body
-These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division

A

Acquired (somatic/sporatic)

-Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation

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3
Q

Types of mutations at the chromosome level

A
  • Deletions
  • Duplications
  • Inversions
  • Translocations t[#,#]
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4
Q

encodes a cytoplasmic tyrosine kinase

A

C-abl

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5
Q

promotes oligomerization

A

Bcr

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6
Q

promotes activation of
abl by oligomerization induced autophosphorylation

A

Bcr-abl fusion

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7
Q

What is the most common variant with Burkitts Lymphoma?

A

T(8;14)(q24;q32)

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8
Q

What is Burkitts lymphoma associated with?

A

the Epstein-Barr Virus
(EBV) in nearly 100% of cases in endemic form in central Africa.
* In the sporadic forms (occur in Western countries), EBV is present in approximately 30% of cases and in 40% of immunodeficiency-associated
cases

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9
Q

Burkitts Lymphoma T(8;14)(q24;q32):

______ is brought under the
transcriptional control of the IG enhancer elements leading to its constitutive transcriptional deregulation

A

MYC

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10
Q

Base substitutions (Point Mutation)
* ____________ (purine for purine, pyrimidine for pyrimidine)
* ____________ (purine for pyrimidine)

A

transition

transversion

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11
Q

Type of mutation:

amino acid Condon to “stop”

A

Nonsense mutations

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12
Q

What are the three stop codons?

A

UAA, UAG, UGA

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13
Q

A genetic variant which results in a shorter version of the protein being produced

A

Truncated protein

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14
Q

Example of nonsense mutation

A

Thalassemia
* beta-thalassemia in Sardinia, Codon 40, CAG (Gln) to TAG (stop), Mutation associated with Low LDL
* alpha-thalassemia: Constant Spring: from stop codon to glutamine @ 142 (TAA to CAA)

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15
Q

Multiple gene deletions also termed

A

CATCH 22

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16
Q

Multiple gene deletions:

What does CATCH 22 an acronym for?

A

Microdeletions in chromosomal region
22q11.2 (CATCH 22)

cardiac defect, abnormal
facies, T-cell deficit, cleft palate, and hypocalcemia.

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17
Q

What are two examples of multiple gene deletions?

A

-DiGeorge syndrome
-Velocardiofacial syndrome

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18
Q

Frame-Shift mutations are _____________, not multiple of 3bp

A

insertion/deletion

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19
Q

Examples of frame-shift mutations

A

e.g., Tay Sachs 4 bp insertion,
* BRCA1 185 delAG, BRCA2 6174delT, etc.
* Blood group O (1 bp deletion)

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20
Q

What are other types of mutations?

A
  • Cap-site Mutants
  • Mutations in initiation codons
  • Creation of a new initiation codon
  • Mutations in termination codons
  • Polyadenylation/cleavage signal mutations.
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21
Q

Factor V Leiden Pathophysiology:

In the normal person, factor V functions as a cofactor to allow factor _____ to activate an enzyme called thrombin. Thrombin in turn cleaves
fibrinogen to form fibrin, which form the fibrin clot.

A

Xa

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22
Q

Factor V Leiden Pathophysiology:

Activated protein _______ is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V.

A

C (aPC)

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23
Q

Factor V Leiden Pathophysiology:

The excessive clotting that occurs in this disorder is almost always restricted to the…

A

veins, where the clotting may cause a deep vein
thrombosis (DVT)

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24
Q

How common is Factor V Leiden in Caucasians in North America?

A

5%

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25
Q

What causes increased clotting with Factor V Leiden?

A

protein C cannot inhibit factor 5 —> increased clotting

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26
Q

What is the inheritance type for Factor V Thrombophilia ?

A

autosomal dominant condition that exhibits
incomplete dominance

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27
Q

Factor V thrombophilia results in a factor V _____ that cannot be as easily degraded by activated protein C.

A

variant

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28
Q

What is the gene responsible for Factor V thrombophilia pathology?

What chromosome?

A

F5, single nucleotide polymorphism

Chromosome 1 in exon 10

-A single nucleotide polymorphism (SNP) located in exon 10.

29
Q

FV Thrombophilia:

A missense substitution of base ________, changes the protein’s amino acid from arginine to ____________***

A

G1691A

glutamine (R506Q)

30
Q

What is the result of the mutation seen with FV thrombophilia?

A
  • deplete the protein C binding site in the Coag pathway
  • removes a cleavage site of the restriction endonuclease MnlI
31
Q

Factor V Leiden:

The mutation (a
1691G→A substitution)
removes a cleavage site
of the restriction
endonuclease _____

A

MnlI,

PCR products treat with MnlI

32
Q

Unstable trinucleotide repeat examples

A
  • Fragile X Syndrome (CGG)n 5’UT
  • Huntington’s syndrome (CAG)n polyglutamine
  • Myotonic dystrophy (CTG)n 3’UT
  • SCA type 1 (CAG)n polyglutamine
  • Friedrich’s Ataxia (GAA)n intron 1
33
Q

The most common cause of inherited intellectual disability and the most
common known genetic cause of autism or autism spectrum disorders

A

Fragile X Syndrome

34
Q

Fragile X syndrome occurs in approximately 1 in_______ males and 1 in ________
females.

A

4,000

8,000

35
Q

Fragile X syndrome mutation is in the ______ gene

A

FMR1

-FMRP

36
Q

What is the FMRP regulate?

A

the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells.

37
Q

How is fragile X-CGG expansion mutations detected?

A

by PCR and Southern Blot

38
Q

An autosomal dominant and almost fully penetrant inherited disorder with
progressive brain dysfunction that causes uncontrolled movements,
emotional problems, and loss of thinking ability (cognition).***

A

Huntington’s Disease

39
Q

How prevalent is Huntington’s disease in people of European ancestry?

A

estimated 3 to 7 per 100,000 people

40
Q

What is the mutation that causes Huntington’s disease?

A

CAG trinucleotide repeats in coding region**

41
Q

The ______ gene product is called huntingtin protein.

A

HTT

42
Q

Huntington’s Disease:

  • An increase in the size of the CAG segment (>40) leads to the production of an
    abnormally long version of the huntingtin protein.
  • The elongated protein is cut into smaller,______ fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells
A

toxic

43
Q

What does CFTR stand for?

A

Cystic Fibrosis Transmembrane
Conductance Regulator

44
Q

Frequency of people who carry the CF gene is about…

A
  • 1 in 29 Caucasian Americans;
  • 1 in 46 Hispanic Americans;
  • 1 in 65 African Americans; and
  • 1 in 90 Asian Americans.
45
Q

What are clinical features of cystic fibrosis?

A

Chronic Sinusitis, Pancreatic insufficiency (malnutrition), Airflow obstruction
Recurrent infection (Psa, S. aureus), Obstructive azoospermia (CBAVD)

46
Q

What is the role of the CFTR protein?

A

To allow chloride ions to exit the mucus-producing cells.
* When the chloride ions leave these cells, water follows, thinning the mucus, allowing the mucus to be moved steadily along the passage ways to aid in cleansing.

47
Q

in CF, the defective ______
protein does not allow chloride ions out of mucus-producing cells.

A

CFTR

48
Q

The CF Gene: Vital Statistics

  • Complete gene locus spans ____ kb
  • ___ exons
  • Mature mRNA of _______bases
A

250
27
6,500

49
Q

CF Gene encodes an ion channel of _______ amino acids.

A

1,480

50
Q

What is the inheritance pattern of CF?

A

autosomal recessive***

51
Q

characterized primarily by progressive lung disease, pancreatic insufficiency, gastrointestinal obstruction and an excess of sodium and chloride in the sweat.

A

Cystic Fibrosis

52
Q

A defect of _________ gene causes all the consequences of CF.

Over ________ known defects in the CFTR gene that can cause CF.

A

single

2,000

53
Q

Cystic Fibrosis:

Three-nucleotide deletion of codon _______ in 70% patients

A

508 (phe)

54
Q

Major Mutations of CF:

_______ mutation leads to improper processing and intracellular degradation of the CFTR protein.

A

Delta F(508)

55
Q

Major Mutations of CF:

Other mutations in the CF gene produce fully processed CFTR proteins that are either ____________ or ___________.

A

non-functional or partially
functional

56
Q

True or false:

The screening tests for CF is not done as part of the standard newborn screening

A

False.

part of standard newborn screening tests

57
Q

Traditional Screen Test (IRT) for CF:

The screening test looks for elevated levels of a substance called _______________, which is an enzyme produced by the pancreas.

A

immunoreactive trypsinogen (IRT)

58
Q

In people with cystic fibrosis (CF),___________ can block the pancreatic ducts that lead into the small intestine, preventing trypsinogen from reaching the intestine and preventing the breakdown of food proteins

A

mucous plugs

59
Q

What is done if the Traditional Screen Test (IRT) for CF is positive?

A

a sweat chloride will be done

60
Q

What is the gold standard for CF testing?

A

sweat chloride test, or sweat test

61
Q

What does the sweat chloride test measure?

A

the amount of salt in a person’s sweat, which is higher than normal in people with CF.

62
Q

What is considered positive for a sweat chloride test?

A

A chloride content greater than 60 mmol/liter***

63
Q

Why would a doctor order a sweat chloride test when the IRT levels are elevated but no CFTR mutation was detected?

A

in case the baby
has one of the less common mutations that was not included in the genetic
testing panel.

64
Q

What does ASO stand for?

A

Allele-Specific Oligonucleotide probes

65
Q

ASO (n) probe =
ASO (x) probe =

A

WT (wild type)
mutant

66
Q

Genetic Testing Complexities:

a single genetic mutation results in a range of phenotypes.

A

Variable expressivity

67
Q

Genetic Testing Complexities:

the same phenotype results from mutations in different genes (includes diseases with multiple genetic components)

A

Genetic heterogeneity

68
Q

Genetic Testing Complexities:

mutation is present without the predicted phenotype.

A

Penetrance

Molecular Diagnostics (12 decks)

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