HD Genetic Testing
Genetics of HD-Mode of Inheritence
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Genetic study of a Huntington's disease phenocopy

 Mode of inheritance:

  • Autosomal dominant (from parent to child)
  • 50% chance of inheriting from gene-carrying parent
  • Greater chance of earlier onset when inheriting from father

Gene characteristics:

  • Identified in 1993
  • Located on the short arm of chromosome 4
  • Gene codes for large protein, called huntingtin
  • Expanded and unstable repeats of the trinucleotide, CAG
  • Normal and abnormal functioning is under investigation
  • There is an inverse relationship between CAG repeat length and age of onset of HD
  • CAG repeat length accounts for approximately 50% of the variation in age of onset
Direct Gene Test Results
  • Requires pre-test genetic counseling
  • 99% of individuals with HD have CAG repeat lengths within the HD range
  • Results may vary from lab to lab
  • Pre-test genetic counseling
    • Educational & supportive counseling
    • Requires time to learn the implications
    • May require some family participation
    • May reveal non-paternity
    Post-test genetic counseling
    • Provide educational & supportive counseling
    • Allow time to express feelings about impact of test result
    • Encourage adherence to post-test plan

    •  Normal CAG repeat length

     < 30

     Intermediate CAG repeat length, not clearly defined, not interpretable

     "Gray zone - under investigation

     CAG repeat length in HD range

     > 39

    Genetics of Huntingtons Disease
    Expanded trinucleotide repeat (CAG) on gene on short arm of chromosome 4 (4p16.3)

    CAG length greater than 38 repeat confers high probability (99%) for carrying HD gene

    The range for indeterminate and low probability HD gene carrier status have not been firmly established

    There is an inverse correlation between CAG and age of onset, but much of the correlation is accounted for by juvenile onset disease (>50 repeats)

    Repeat length accounts for 50% of the variance of age of onset has not been found to correlate consistently with clinical features or progression of HD

    Expansion is unstable, CAG repeat length can be markedly expanded during spermatogenesis

    Brickman etal., (Am J Hum Gen 1997:60)
    CAG size was inversely related to age of onset r2=0.73 (p<0.001)
     
    Median age of onset decreased by 3.4 years+/-2 for each repeat length 39-54
    Lower limit of CAG repeat size in individuals who manifest with HD is 36
    Complete penetrance with CAG repeat >/= 42
    Sporadic HD

    New mutations occur in 1-3% of HD cases

    Unstable expansion that occurs during spermatogenesis means that siblings of sporadic cases are at risk, and children of unaffected siblings with the intermediate allele are also at risk 4/9 elderly unaffected relatives of sporadicHD cases had repeat lengths in 34-38 range (Myers etal., Nature Genetics 1993)

    CAG Repeat Ranges

     Category

    CAG Repeat Range 

     Phenotype

     Normal Allele

     </=26

     Normal

     Mutable Normal Allele

     27-35

     Normal

     HD Allele with Reduced Penetrance

     36-39

     Normal/HD

     HD Allele

     >/=40

     HD
    Categorization of CAG Repeat Length in At-Risk Individuals

     CAG Repeat Length

    Category of Results

    40, or greater

    high probability of HD 

    30-39 

    indeterminate 

    29 or fewer 

    low probability 
    Categorization of CAG Repeat Length in Symptomatic Individuals

    CAG Repeat Length

     Category of Results

     38 or greater

     high probability of HD

     30 - 37

     indeterminate

     29 or fewer 

     low probability of HD
    Genetics of HD

    Mutable normal allele (27-35) refers to repeat lengths with demonstrated meiotic instability in sperm which have not been associated with the HD phenotype. They may transmit HD to their offspring
    reduced penetrance (36-39)

    May or may not manifest HD, but those alleles may be meiotically unstable and carriers may transmit to their offspring.

    Children

    Children and juveniles with HD have a much higher risk (75-80%) of having inherited their mutant gene with expanded CAG repeats from their father sex-specific effect on the likelihood of expansion of CAG repeat when passed from affected father to child expansions of CAG also do occur when passed from affected mother to child - but generally the expansion is not to the degree to cause juvenile HD, unless the mother of the child has juvenile HD
    Genetics of HD and Therapeutics

    The goal of therapeutic trials alter the median age of onset extension of the age at which all persons with that repeat length would be expected to manifest HD

    Issues Raised by a Direct Test for Huntingtons Disease

    Does having a gene constitute having a disease at a time when the person is completely asymptomatic?

    Issues of confidentially and autonomy
    Testing a person at 25% risk if the person does not want to know his or her status monozygotic twins prenatal testing  Testing minors for a condition for which there is no intervention

    Huntington gene codes for protein huntingtin
    CAG repeat codes for glutamine
    Normal function of huntingtin protein is unknown.  Expanded protein is known to retain     activity