Huntington's Disease Genetic Testing and Disease Development
Yes, a person with a positive genetic test for Huntington's disease may not develop symptoms if their CAG repeat count falls within the reduced penetrance range of 36-39 repeats. 1
Understanding CAG Repeat Ranges and Disease Manifestation
Huntington's disease (HD) is caused by an expansion of CAG trinucleotide repeats in exon 1 of the HTT gene. The number of repeats determines whether and when an individual will develop symptoms:
- Normal alleles (≤26 CAG repeats): Never associated with HD phenotype 1, 2
- Mutable normal alleles (27-35 CAG repeats): Not associated with HD symptoms but may expand in future generations, particularly through paternal transmission 1
- Reduced penetrance alleles (36-39 CAG repeats): Associated with HD in some individuals but not others - this is the key range where a positive test may not lead to disease development 1, 2
- Full penetrance alleles (≥40 CAG repeats): Disease is fully penetrant, meaning symptoms will eventually develop if the person lives a normal lifespan 1, 2
Reduced Penetrance Range (36-39 CAG Repeats)
The reduced penetrance range is particularly important in answering this question:
- Individuals with 36-39 CAG repeats have been reported in both clinically affected and clinically unaffected individuals 1
- In rare cases, elderly individuals with alleles in this range have remained asymptomatic throughout their lives 1
- For these individuals, it's impossible to determine with certainty whether they will develop HD symptoms 1
Full Penetrance Range (≥40 CAG Repeats)
For individuals with ≥40 CAG repeats:
- The disease is considered fully penetrant 1, 2
- Symptoms will eventually develop if the person lives a normal lifespan
- However, the guidelines do note that there has been at least one documented case of an individual with ≥40 CAG repeats who died disease-free after living to or past normal life expectancy 1
Clinical Implications
- Genetic testing for HD has several applications: diagnostic confirmation, predictive testing, and prenatal testing 2
- Tests that effectively detect and measure the CAG repeat region are >99% sensitive 1
- Positive results with ≥40 CAG repeats are 100% specific for HD diagnosis 1, 2
- For alleles in the 36-39 range, it's not possible to determine the specificity of the test 1
Important Considerations for Genetic Testing
- Predictive testing should not be offered to individuals until they are at least 18 years old 1
- A formal multidisciplinary predictive testing protocol should be offered to individuals desiring determination of their carrier status 1, 2
- The age of onset correlates inversely with CAG repeat length - longer repeats typically lead to earlier onset 2
Pitfalls and Caveats
- A positive genetic test with 36-39 CAG repeats cannot definitively predict whether an individual will develop HD
- Even with ≥40 CAG repeats, the age of symptom onset can vary considerably
- Genetic counseling is essential before and after testing to help individuals understand the implications of their results, especially for those with repeat counts in the reduced penetrance range
- The absence of symptoms does not mean an individual with a positive test (≥40 repeats) will never develop the disease - symptoms may develop later in life
In summary, while Huntington's disease is generally considered fully penetrant at ≥40 CAG repeats, individuals with 36-39 repeats may never develop the disease despite having a positive genetic test.