Unstable
Repeat Expansions
Huntington
Myotonic dystrophy
Friedreich ataxia
Epidemiology and
Etiology:
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Repeating units of 3 or more nucleotides in tandem
·
Within a gene generally (those that cause disease)
·
Polymorphic in general
·
Number of repeats can expand as it is passed from generation to
generation
·
Likely due to slipped mispairing (a DNA
replication error)
·
Results in anticipation, and parental transmission bias
·
In most, maternal inheritance is associated with repeat expansion
·
In HD, it is paternal inheritance
·
Expansion can occur during meiosis and mitosis
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More than a dozen diseases known to be caused by such a mechanism
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Primarily neurological
·
Inheritance pattern varies
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Pathogenesis mechanisms:
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Class 1: expansion of noncoding repeats
that impair transcription of the preRNA from the
affected gene
·
Fagile X
·
Friedreich ataxia
·
Class 2: expansion of noncoding repeats
that confer novel properties on the RNA
·
Myotonic dystrophy 1 and
2
·
Fragile X-associated tremor / atalxia
syndrome (FXTAS)
·
Class 3: repeat expansion of a codon
that confers novel properties on the affecte protein
·
HD
·
Spinocerebellar ataxias
Common sites:
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Gross features:
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Histologic
features:
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Immunophenotype:
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Marker: |
Sensitivity: |
Specificity: |
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Molecular features:
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Other features:
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References:
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Nussbaum RL, McInnes RR, Willard HF.
Thompson & Thompson Genetics in Medicine: With STUDENT CONSULT Online
Access. 7th ed. Saunders; 2007:600.