Lecture 6: Clinical DNA Diagnosis Flashcards

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1
Q

Types of Point Mutations (Single Base Substitutions)

A
  1. Silent Mutation
  2. Nonsense Mutations
  3. Missense Mutations
  4. Splice Site
    Mutations
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2
Q

Silent Mutation

A

Base pair change does not alter the amino acid sequence due to redundancy (wobble) in the genetic code.

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3
Q

Nonsense Mutations

A

Replace an amino acid with a stop codon.

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4
Q

Missense Mutations

A

Replace one amino acid with another in the gene product.

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5
Q

Splice-Site Mutation

A

Creates or destroys signals for exon/intro splicing.

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6
Q

Deletion

A

Mutation that results in an absence of a portion of a DNA sequence (usually in coding DNA or regulatory sequences).

Ranges from 1 base pair to millions of base pairs.

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7
Q

Insertions

A

Mutation that results in an extra DNA sequence within the coding sequence of a gene.

Ranges from 1 base pair to millions of base pairs.

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8
Q

Frameshift Mutation

A

Mutation that can be produced by deletions, insertions, or splicing errors resulting in the shift of the reading frame.

Often results in a stop codon that produces a truncated polypeptide.

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9
Q

Promoter Mutation

A

Mutation affecting the binding of RNA polymerase to the promoter site.

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10
Q

Duplication

A

A type of insertion due to repeated regions of DNA.

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11
Q

Expansion of Tandem Repeat Sequences

A

An increase of a normal, small number of repeats (20-30 copies of a short sequence such as CGC) to a dramatically larger number (100s or 1000s). Can cause genetic diseases usually with genetic anticipation.

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12
Q

Loss of Function (LOF) Mutations

A

Mutations that result in protein products that have reduced function, no function, and/or may interfere with the function of the normal product.

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13
Q

Three types of LOF mutations:

A
  1. Classical Recessive Inheritance
  2. Haploinsufficiency
  3. Dominant-negative Mutations
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14
Q

Classical Recessive Inheritance (LOF)

A

For many genes, the amount of protein produced by the gene is not crucial for a normal biological outcome.

Even 40-50% of normal protein production is sufficient.

Must inherit both abnormal alleles.

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15
Q

Haploinsufficiency (LOF)

A

Occurs when half (haplo) of the normal gene product is insufficient for completely normal biological function.

Autosomal dominant, incompletely dominant. Two abnormal copies gives rise to more serious phenotypes.

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16
Q

Dominant-Negative Mutations (LOF)

A

Mutations that result in a mutant product from one allele that not only loses its original function, but also prevents the product of the other, normal allele from functioning in a heterozygous individual.

17
Q

Gain of Function Mutations

A

Mutations that cause the protein product to be overproduced or to actively function in a new, abnormal way.

i.e. Achondroplasia (receptor turned on and stuck–no chondrocyte proliferation–short bones).

18
Q

Four benefits of DNA-based tests?

A
  1. Definitive diagnosis.
  2. Pre-symptomatic diagnosis.
  3. Pre-implantation or pre-natal diagnosis.
  4. Genotype-phenotype correlations.
19
Q

Five challenges of DNA-based tests?

A
  1. Heterogeneity
  2. Allelic disorders
  3. Variable Expression
  4. Non-paternity exposure
  5. Genetic discrimination
20
Q

Direct Mutation Testing

A

The optimal, but not always practical method of DNA-based diagnosis.

21
Q

Specimen

A

DNA samples are obtained from the individual from places such as blood, skin, cheeks, semen, etc. In prenatals, CVS, amniocentesis, or maternal cell-free fetal DNA.

A type of direct DNA testing.

22
Q

Karyotype Analysis

A

The chromosomes are examined under a microscope for duplications, deletions, or translocations of large segments of DNA. Less than 3 Mbp cannot be detected.

A type of direct DNA testing.

23
Q

FISH

A

Flourescent in situ Hybridization.

Used to look for well-defined common deletion or duplication syndromes. Can confirm smaller deletions/duplications by microarray.

A type of direct DNA testing.

24
Q

Methylation Specific RT-PCR

A

Methylation specific reverse transcriptase polymerase chain reaction.

Then differentiates segments of DNA that are methylated and those that are not.

A type of direct DNA testing.

25
Q

Chip Technology

A

Automated technique that is useful for screening large genes with many different mutations.

Also called microarray or array comparative genomic hybridization.

A type of direct DNA testing.

26
Q

Direct Sequencing

A

Used to look for disease-causing mutations within a given gene.

A type of direct DNA testing.

27
Q

Allele Specific Oligonucleotide Testing

A

Commonly used to look for a panel of common mutations in a given gene or several genes.

A type of direct DNA testing.

28
Q

STRPs

A

Short Tandem Repeat Polymorphisms.

The use of just 13 STRPs allows for a match probability of one in a trillion. Used in crime scenes and paternity testing.

A type of direct DNA testing.

29
Q

MLPA

A

Multiple Ligation-Dependent Amplification.

Allows for the detection of multiple regions of DNA at the same time, using one set of PCR primers. Can be used to detect large deletions, small deletions, and even single base pair changes.

A type of direct DNA testing.

30
Q

Southern Blot

A

Useful in detecting DNA fragments of variable lengths. Tests for TNT repeat disorders.

A type of direct DNA testing.

31
Q

RFLP

A

Restriction Fragment Length Polymorphisms.

Used to test for disease that are caused by mutations that occur at specific restriction sites.

A type of direct DNA testing.

32
Q

Next-Gen Sequencing

A

Uses the latest automated sequencing to sequence the entire genome in just days for a few thousand dollars. Will revolutionize medicine.

A type of direct DNA testing.

33
Q

Indirect Mutation Testing

A

Used in clinical scenarios where the disease gene is not yet known, rendering direct DNA testing impossible. Often requires large families to be informative.

34
Q

What is the difference between screening and testing?

A

Screening is the process of identifying people who are at higher-than-usual risk for a disease, but are not affected yet.

Testing is the process of targeted disease-specific lab procedures to definitively establish that someone is or is not affected.

35
Q

Population screening can detect…

A

mutations pre-symptomatically to allow for better outcomes.