Genetic Testing 1&2; Mutational Mechanisms Flashcards
What novel mutational mechanism do trinucleotide repeat expansion disorders share?
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.
Why do trinucleotide repeat disorders not follow Mendelian inheritance?
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.
What is the most common inherited form of mental retardation? What is it’s mode of inheritance?
Fragile X Syndrome
X-linked inheritance
Explain the trinucleotide repeat expansion disorder associated with Fragile X Syndrome.
CGG expansion in 5’ untranslated region of FMR1 gene; expansion accompanied by DNA methylation, which shuts down gene expression.
6-54 CGG repeats would result in a normal or affected allele?
Normal allele (Stable)
55-200 CGG repeats would result in a normal or mutated allele?
Pemutated allele (Stable/unstable)
200-1300 CGG repeats would result in what disorder?
Fragile-X Allele (unstable)
The expansion of permutation alleles to full allele size in Fragile X Syndrome only occurs during male or female meiosis?
Female
Fragile X Syndrome’s trinucleotide repeat expansion occurs in a coding or noncoding region or DNA?
Noncoding. The expansion within the noncoding region interferes with normal gene expression causing a loss of function.
Polyglutamine [(CAG)n] tracts in coding sequences lead to neuronal degeneration. Give an example of such a disease.
Huntington Disease
Polyglutamine tracts are associated with gain or loss of function mutations?
Gain of function
Explain, on a molecular level, what happens from genetic coding to pathogenesis in Huntington disease.
(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
Would 6-34 repeats of CAG on HD 4p16.3 result in a stable allele or Huntington disease?
Stable allele
36-100+ repeats of CAG on HD 4p16.3 would result in meiotic instability presenting as:
Huntington Disease
What is Huntington Disease’s mode of inheritance?
Autosomal Dominant
As a genotype/phenotype correlation in Huntington Disease, age of onset is associated with:
Number of CAG repeats. Higher # = lower age of onset
In contrast to fragile x syndrome, Huntington Disease is associated with greater meiotic expansion in __________.
Male meiosis
In trinucleotide repeat expansion disorders, can allele sizes continue to increase from one generation to the next?
Yes.
Anticipation in repeat expansion disorders refers to:
Grandma, pissed off, not retarded. Mom, kinda retarded. Grandson, full blown retard. Anticipate that shit.
What is the analytic validity of a genetic test?
accuracy of the test
What is the clinical validity of a genetic test?
ability of a test to predict outcome
What is the clinical utility of a genetic test?
ability of the test to improve the outcome
What are the additional implications of genetic testing?
ethical, social, and legal
What is cascade screening?
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
What is direct testing?
primary test for a suspected mutation screening, but relies on a defined mutation panel and is limited to the alleles that are tested
How are trinucleotide repeats tested for?
direct testing by allele sizing; it is gene-specific and relies on PCR amplification across the repeat region
How is Huntington disease tested?
since HD is a trinucleotide repeat syndrome, use direct testing by sizing the allele
Is expansion of at-risk alleles predictable from generation to generation?
No.
What are the most significant distinctions between the two categories of trinucleotide repeat expansion disorders?
LOF vs. GOF, and repeat located in coding vs. non-coding sequence
