Genetics of Huntington’s Disease

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

• 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	Post-test genetic counseling
  Educational & supportive counseling Requires time to learn the implications May require some family participation May reveal non-paternity	Provide educational & supportive counseling Allow time to express feelings about impact of test result Encourage adherence to post-test plan

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

---

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 “sporadic”HD cases had repeat lengths in 34-38 range (Myers etal., Nature Genetics 1993)

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 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

Issues Raised by a “Direct” Test for Huntington’s 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