Huntington’s disease is caused by a trinucleotide repeat expansion mutation in the HTT gene on chromosome 4. Specifically, a three-letter DNA sequence, CAG, repeats far more times than normal, producing a defective protein that gradually destroys nerve cells in the brain. This places Huntington’s in a small family of genetic disorders driven by the same basic glitch: a short stretch of DNA that stutters and copies itself too many times.
How the CAG Repeat Expansion Works
DNA is written in three-letter “words” called codons, and CAG is the codon that tells the cell to add the amino acid glutamine to a protein. In a healthy copy of the HTT gene, the CAG segment repeats 10 to 35 times. That’s normal variation. In someone with Huntington’s, the segment repeats 36 to more than 120 times, creating an abnormally long stretch of glutamine in the resulting huntingtin protein.
Not every expansion guarantees disease. The ranges break down into distinct categories:
- 10 to 35 repeats: Normal. No risk of Huntington’s.
- 36 to 39 repeats: A gray zone. Some people in this range develop symptoms, others never do. Geneticists call this “reduced penetrance.”
- 40 or more repeats: Full penetrance. A person with this count will almost always develop the disease at some point in their life.
The number of repeats also influences when symptoms appear. In adult-onset Huntington’s, CAG repeat length accounts for roughly 57 to 59% of the variation in the age when motor symptoms begin. In juvenile-onset cases (symptoms before age 20), the relationship is even tighter: repeat length predicts about 84% of the variation in onset age, according to data from the Kids-JOHD study. In practical terms, higher repeat counts mean earlier, often more severe disease.
Why This Mutation Is Classified as Autosomal Dominant
Huntington’s follows an autosomal dominant inheritance pattern. You have two copies of the HTT gene, one from each parent. A single expanded copy is enough to cause the disease. If one of your parents carries the mutation, you have a 50% chance of inheriting it. Unlike recessive conditions, there’s no “carrier” state where you have the mutation but are protected by a normal second copy.
This is one reason Huntington’s is so difficult for families. Every child of an affected parent faces a coin-flip probability, and because symptoms typically appear in the 30s or 40s, many people have already had children before they know they carry the expansion.
Genetic Anticipation and Paternal Transmission
One unsettling feature of trinucleotide repeat mutations is that they can grow longer from one generation to the next, a phenomenon called genetic anticipation. When a parent passes the HTT gene to a child, the CAG stretch can expand further, meaning the child may develop symptoms earlier and more severely than the parent did.
This expansion tends to be more dramatic when the mutation is inherited from the father. Research published in the Journal of Medical Genetics found that major anticipation is heritable through the male line, likely related to differences in how DNA is copied during sperm production versus egg production. Sperm cells undergo many more rounds of division over a man’s lifetime, giving the repeat more opportunities to slip and expand. This paternal bias helps explain why juvenile Huntington’s, which involves very high repeat counts, is more commonly inherited from fathers.
Somatic Expansion: The Mutation Keeps Growing
The CAG repeat you’re born with isn’t necessarily the one your brain cells carry decades later. Research in Human Molecular Genetics found that the expanded repeat continues to grow within certain tissues over a person’s lifetime, a process called somatic instability. This is especially pronounced in the striatum and cortex, the exact brain regions that are hit hardest by the disease.
In cortical brain tissue from 48 Huntington’s patients, roughly 50% of mutant HTT copies had expanded by at least one additional CAG repeat beyond the inherited length. Most changes were further expansions rather than contractions. This ongoing expansion in the brain appears to accelerate disease progression: individuals with greater somatic instability in their brain tissue tended to develop symptoms earlier than their inherited repeat length alone would predict. The cell’s own DNA repair machinery, particularly mismatch repair proteins, seems to drive these additional expansions, which is an active area of investigation for potential treatments.
How the Mutant Protein Damages Brain Cells
The expanded CAG repeat produces a huntingtin protein with an abnormally long glutamine tail. This altered protein misfolds and clumps into aggregates inside nerve cells. These clumps cause damage through several overlapping mechanisms.
First, the protein aggregates interact with cell membranes and can form pore-like structures that let excess calcium flood into the cell. The cell then burns extra energy trying to pump that calcium back out, which generates harmful byproducts called reactive oxygen species. These byproducts damage DNA, fats, and other proteins, creating a cycle of worsening cellular stress.
Second, the aggregates physically disrupt the endoplasmic reticulum, the cell’s protein-manufacturing system. In regions where mutant huntingtin fibrils contact the ER, the machinery for building and quality-checking new proteins is displaced. This stalls normal protein production and causes additional misfolded proteins to pile up.
Third, the clumps overwhelm the cell’s waste-disposal system. Cells normally tag damaged proteins with a small molecule called ubiquitin, marking them for destruction. Mutant huntingtin aggregates absorb free ubiquitin “like a sponge,” starving the rest of the cell of the tags it needs to clear out its normal waste. The result is a toxic buildup of proteins that would otherwise be recycled. They also trap functional proteins and genetic material in stress granules, further crippling normal cell operations. Together, these effects gradually kill neurons, particularly in brain regions controlling movement, cognition, and emotion.
Genetic Testing and What the Results Mean
A simple blood test can determine the number of CAG repeats in your HTT gene. Results fall into the categories described above: under 36 is normal, 36 to 39 is uncertain, and 40 or above confirms you will likely develop the disease. Because this test delivers a life-altering answer with no current way to prevent or cure the condition, genetic counseling before and after testing is standard practice.
Predictive testing, meaning testing someone without symptoms who has a family history, is generally reserved for adults 18 and older. Major Huntington’s advocacy and medical organizations strongly discourage testing minors, not by law but by ethical consensus: the reasoning is that children lack the maturity to make an informed choice about learning their status for a condition with no disease-modifying treatment. The exception is when a child or adolescent shows symptoms suggestive of juvenile-onset Huntington’s, in which case diagnostic testing may be appropriate after other conditions have been ruled out.