What is the genetic basis of Huntington's disease and how is it inherited?

Genetic Basis and Inheritance of Huntington's Disease

Huntington's disease (HD) is caused by an autosomal dominant expansion of CAG trinucleotide repeats in exon 1 of the HTT gene located on chromosome 4p16.3, with full penetrance occurring when repeat numbers reach 40 or greater. 1

The HTT Gene and Mutation

The HTT gene (historically known as IT15) spans 170 kb and contains 67 exons. It encodes the huntingtin protein, which:

• Has 3,144 amino acid residues
• Has a molecular weight of 350 kDa
• Lacks homology to previously known proteins 1

The disease-causing mutation involves:

• Expansion of a polymorphic CAG repeat in exon 1
• Translation of this expanded repeat into a polyglutamine tract in the huntingtin protein
• Resulting in protein misfolding, nuclear accumulation, and aggregation of HTT fragments 1

CAG Repeat Categories and Clinical Correlation

The number of CAG repeats determines disease manifestation:

1. Normal alleles (≤26 CAG repeats):

   • Never associated with HD phenotype
   • Most common normal allele lengths contain 17 and 19 CAG repeats 1

2. Mutable normal alleles (27-35 CAG repeats):

   • Rare and not convincingly associated with HD phenotype
   • May be unstable and expand in future generations 1

3. Reduced penetrance alleles (36-39 CAG repeats):

   • Variable penetrance
   • Reported in both clinically affected and unaffected individuals
   • Cannot determine test specificity in this range 1

4. Full penetrance alleles (≥40 CAG repeats):

   • Disease appears fully penetrant
   • 100% specific for HD diagnosis 1

Inheritance Pattern

HD follows an autosomal dominant inheritance pattern, meaning:

• Only one copy of the mutated gene is needed to cause the disease
• Each child of an affected parent has a 50% chance of inheriting the mutation
• The disease affects males and females equally 1, 2

Genetic Anticipation

An important characteristic of HD inheritance is genetic anticipation:

• CAG repeats can expand when transmitted from parent to child
• Paternal transmission is more likely to result in expansion
• This can lead to earlier onset in subsequent generations
• Particularly significant in juvenile-onset HD (onset before age 20), which represents approximately 5% of cases 1, 2

Genetic Testing

Genetic testing for HD has several applications:

• Diagnostic testing: Confirms HD in symptomatic individuals
• Predictive testing: Determines carrier status in asymptomatic at-risk individuals
  • Should not be offered until individuals are at least 18 years old
  • Should be conducted within a formal multidisciplinary testing protocol 1
• Prenatal testing: Available for amniotic fluid cells and chorionic villus samples
  • Requires confirmation of fetal origin through maternal cell contamination studies
  • Evidence of molecular diagnosis in the family should be obtained first 1

Clinical Implications of Genetics

The CAG repeat length influences clinical presentation:

• Longer CAG repeats correlate with earlier disease onset
• Juvenile-onset HD (onset before age 20) typically has very large expansions
• Presents with rigidity and spasticity rather than chorea
• Shows more rapid disease progression 1, 2

The genetic mutation leads to selective neuronal loss, particularly in the caudate nucleus and putamen, resulting in the classic triad of:

• Motor symptoms (typically chorea)
• Cognitive decline
• Psychiatric disturbances 2

Genetic Testing Considerations

When considering genetic testing:

• Tests that effectively detect and measure the CAG repeat region are >99% sensitive
• Positive results with ≥40 CAG repeats are 100% specific
• Genetic counseling is essential before and after testing
• Testing should be performed in specialized centers with appropriate support 1

The definitive diagnosis of HD requires both clinical symptoms and confirmation of CAG expansion in the HTT gene, as this mutation accounts for >99% of HD cases 1, 2.