Genetic Testing 1&2; Mutational Mechanisms

Question 0

What novel mutational mechanism do trinucleotide repeat expansion disorders share?

Answer 0

Genes containing tandem repeats of 3 basepairs. Unstable expansion of repeat copy number from one generation to the next. The expansion disrupts normal gene function, causing neurologic disease.

Question 1

Why do trinucleotide repeat disorders not follow Mendelian inheritance?

Answer 1

In high risk families, there can be a change in the genetic makeup within these genes in transmission from parent to child. These are also often called Dynamic Mutations.

Question 2

What is the most common inherited form of mental retardation? What is it’s mode of inheritance?

Answer 2

Fragile X Syndrome

X-linked inheritance

Question 3

Explain the trinucleotide repeat expansion disorder associated with Fragile X Syndrome.

Answer 3

CGG expansion in 5’ untranslated region of FMR1 gene; expansion accompanied by DNA methylation, which shuts down gene expression.

Question 4

6-54 CGG repeats would result in a normal or affected allele?

Answer 4

Normal allele (Stable)

Question 5

55-200 CGG repeats would result in a normal or mutated allele?

Answer 5

Pemutated allele (Stable/unstable)

Question 6

200-1300 CGG repeats would result in what disorder?

Answer 6

Fragile-X Allele (unstable)

Question 7

The expansion of permutation alleles to full allele size in Fragile X Syndrome only occurs during male or female meiosis?

Answer 7

Female

Question 8

Fragile X Syndrome’s trinucleotide repeat expansion occurs in a coding or noncoding region or DNA?

Answer 8

Noncoding. The expansion within the noncoding region interferes with normal gene expression causing a loss of function.

Question 9

Polyglutamine [(CAG)n] tracts in coding sequences lead to neuronal degeneration. Give an example of such a disease.

Answer 9

Huntington Disease

Question 10

Polyglutamine tracts are associated with gain or loss of function mutations?

Answer 10

Gain of function

Question 11

Explain, on a molecular level, what happens from genetic coding to pathogenesis in Huntington disease.

Answer 11

(CAG)n or polyglutamine repeat expansions cause a gain of function mutation in proteins that causes proteins to form toxic aggregates in nuclei of neurons and cause neurodegeneration

Question 12

Would 6-34 repeats of CAG on HD 4p16.3 result in a stable allele or Huntington disease?

Answer 12

Stable allele

Question 13

36-100+ repeats of CAG on HD 4p16.3 would result in meiotic instability presenting as:

Answer 13

Huntington Disease

Question 14

What is Huntington Disease’s mode of inheritance?

Answer 14

Autosomal Dominant

Question 15

As a genotype/phenotype correlation in Huntington Disease, age of onset is associated with:

Answer 15

Number of CAG repeats. Higher # = lower age of onset

Question 16

In contrast to fragile x syndrome, Huntington Disease is associated with greater meiotic expansion in __________.

Answer 16

Male meiosis

Question 17

In trinucleotide repeat expansion disorders, can allele sizes continue to increase from one generation to the next?

Answer 17

Yes.

Question 19

Anticipation in repeat expansion disorders refers to:

Answer 19

Grandma, pissed off, not retarded. Mom, kinda retarded. Grandson, full blown retard. Anticipate that shit.

Question 20

What is the analytic validity of a genetic test?

Answer 20

accuracy of the test

Question 21

What is the clinical validity of a genetic test?

Answer 21

ability of a test to predict outcome

Question 22

What is the clinical utility of a genetic test?

Answer 22

ability of the test to improve the outcome

Question 23

What are the additional implications of genetic testing?

Answer 23

ethical, social, and legal

Question 24

What is cascade screening?

Answer 24

identification of at-risk individuals through systematic family tracing; screening with clinical tests as opposed to all genetic tests; cascade is systematic evaluation of 2nd and 3rd degree relatives

Question 25

What is direct testing?

Answer 25

primary test for a suspected mutation screening, but relies on a defined mutation panel and is limited to the alleles that are tested

Question 26

How are trinucleotide repeats tested for?

Answer 26

direct testing by allele sizing; it is gene-specific and relies on PCR amplification across the repeat region

Question 27

How is Huntington disease tested?

Answer 27

since HD is a trinucleotide repeat syndrome, use direct testing by sizing the allele

Question 28

Is expansion of at-risk alleles predictable from generation to generation?

Answer 28

No.

Question 29

What are the most significant distinctions between the two categories of trinucleotide repeat expansion disorders?

Answer 29

LOF vs. GOF, and repeat located in coding vs. non-coding sequence