A single letter of DNA, repeated too many times. An interactive journey through the HTT gene, the CAG triplet expansion and the inheritance of Huntington's disease.
The entire journey of this page, summarized in six steps.
Before diving into the genetics, it helps to understand the disease that these genes explain.
Huntington's disease is a neurodegenerative, hereditary and progressive disorder that, for now, has no cure. It gradually damages deep brain structures —above all the striatum—, disrupting movement, thinking and behavior in combination.
It is named after George Huntington, who in 1872 described "hereditary chorea" with remarkable clinical precision, based on families from Long Island. For more than a century it was recognized only by its symptoms; in 1993 its cause was identified —the expansion of the CAG triplet in the HTT gene—, the starting point for the rest of this page.
Huntington's combines three broad groups of symptoms that evolve over the years:
Chorea (involuntary, "dance-like" movements), dystonia and, later on, rigidity and slowness. Problems with gait and balance, speech (dysarthria) and swallowing (dysphagia) appear.
Slowing and decline of executive functions (planning, organizing, judging). Over time it evolves into a subcortical dementia; unlike other dementias, episodic memory tends to be relatively preserved in the early stages.
Depression (frequent and with an elevated suicide risk), apathy, irritability, anxiety and obsessive behaviors; sometimes psychosis. They can appear years before the motor symptoms.
Onset between 30 and 50 years. Chorea predominates, alongside the cognitive and psychiatric changes, with a progression of 15–20 years.
Caused by very large expansions (> 60 CAG), almost always inherited from the father (an example of genetic anticipation). Instead of chorea, rigidity and slowness predominate, with seizures and academic decline.
Usually milder and more slowly progressive, with chorea as the main symptom and less cognitive involvement at the start.
Decades can pass between inheriting the gene and the advanced stages. It is a gradual progression, not an abrupt jump.
The person carries the gene but has no symptoms. It can last decades.
Subtle signs years before diagnosis: mood changes and mild motor or cognitive alterations.
Diagnosis based on motor signs. The person is still independent in daily life.
Chorea and the cognitive and psychiatric difficulties limit daily life; independence is lost.
Total dependence, rigidity and dysphagia. Death is usually due to complications (e.g. aspiration pneumonia).
Today, treatment is symptomatic and multidisciplinary: it does not stop the disease, but it improves quality of life. Therapies that attack the cause —the gene and the protein— are reviewed at the end, once the genetics is understood.
VMAT2 inhibitors —tetrabenazine, deutetrabenazine and valbenazine (approved in 2023 for Huntington's chorea)—. Sometimes antipsychotics such as risperidone or olanzapine.
SSRIs for depression and anxiety; antipsychotics for severe irritability or psychosis. Psychiatric management is key to quality of life.
Physical therapy, speech therapy, occupational therapy, nutritional and psychological support, and genetic counseling for the person and their family.
Science-based educational content (George Huntington's clinical description, 1872; identification of the HTT gene, 1993; current clinical practice). It does not replace the assessment of a healthcare professional.
DNA is read in triplets of bases. The HTT gene, on chromosome 4, contains a stretch in which the CAG triplet is repeated over and over. Each CAG codes for the amino acid glutamine.
In most people there are fewer than 27 repeats. When the stretch expands to 40 or more, the huntingtin protein carries an abnormally long tail of glutamines that misfolds, aggregates and becomes toxic to neurons.
Of the 23 pairs of chromosomes, the HTT gene sits at the end of the short arm of chromosome 4, in band 4p16.3. It has 67 exons and spans about 180 kb (its historical name is IT15).
DNA is transcribed into RNA, and this is translated into protein. Each CAG adds a glutamine (Gln). If there are too many CAGs, huntingtin carries a polyglutamine tail that makes it toxic.
The number of CAG repeats determines whether the disease appears and, to a large extent, when. Click each range to see what it means, or use the slider to watch the repeat grow.
It shares its mechanism with other repeat-expansion diseases: a short stretch of DNA repeated too many times. The gene, the "letter" that is repeated and the mode of inheritance change.
| Disease | Gene | Repeat | Threshold | Inheritance |
|---|---|---|---|---|
| Huntington's see → | HTT | CAG | ≥ 36–40 | Autosomal dominant |
| Spinocerebellar ataxia type 1 | ATXN1 | CAG | ≥ 39 | Autosomal dominant |
| Myotonic dystrophy type 1 | DMPK | CTG | ≥ 50 | Autosomal dominant |
| Spinal and bulbar muscular atrophy (Kennedy) | AR | CAG | ≥ 38 | X-linked |
| Fragile X syndrome | FMR1 | CGG | ≥ 200 | X-linked |
| Friedreich's ataxia | FXN | GAA | ≥ ~70 | Autosomal recessive |
Click any row to learn why the same idea —a repeat that grows— produces such different diseases. Many share anticipation (the expansion grows across generations).
The HTT gene decides who will develop Huntington's, but other genes —above all DNA-repair genes— modulate when it begins. They are the new therapeutic targets. Click a card to see the details.
HTT at the center and, around it, the genes that modulate the disease. Hover over a node to identify it; click to see the details.
From the first description of "hereditary chorea" to the HTT gene and the therapies that silence huntingtin.
How mutant huntingtin and the continuous CAG expansion damage neurons, above all in the striatum.
The CAG is not a fixed number: it keeps growing inside neurons with age. Move the age and switch the DNA-repair genes on or off to see how it changes.
Illustrative model of the trend (starting from 40 inherited CAG), not an exact clinical scale.
Click each brain region to see why some are more vulnerable than others.
They make it possible to detect the disease, measure its progression and check whether a therapy is working, objectively:
Illustrative values of the trend, not real clinical scales: NfL and huntingtin start to rise years before the symptoms, while the striatum atrophies progressively.
Huntington's is autosomal dominant: inheriting a single copy of the expanded gene from one parent is enough. Each child has a 50% chance of inheriting it.
That 50% is not an abstract statistic: for many families it is a shadow that shapes major life decisions —parenthood, work, plans for the future—. That is why the genetics of Huntington's is never separated from support and genetic counseling.
The more CAG repeats, the earlier the symptoms tend to appear. In addition, the stretch can expand when transmitted —above all through the paternal line—, so the disease can start earlier in each generation (anticipation).
Adjust the parent's repeats and choose the transmission line. You will see the allele's tendency to grow as it passes to the children.
Illustrative model of the trend, not an individual prediction: the expansion is a random process and varies greatly from one family to another.
It is a statistical trend, not an exact prediction: at the same number of repeats, the age of onset varies widely between people (that is where the modifier genes come in).
The essentials about the genetics of Huntington's disease:
The bottom line: for the first time in the history of this disease, knowing the gene and its mechanism is opening up therapies aimed at the cause, not just the symptoms. Genetics does not only explain Huntington's: it is pointing the way toward its treatment.
It is a purely genetic disease. It is not brought on by lifestyle or environmental factors:
General health can influence how the disease is experienced, but not its cause: that depends solely on the inherited CAG expansion.
Huntington's research is going through its most active moment. This is what is changing right now —and where it is headed—.
Single-cell studies (2024–2025) indicate that the CAG expands slowly over decades within each neuron and only becomes toxic once it crosses a very high threshold (~150 repeats). It would be the somatic expansion, not the inherited allele, that sets the pace of the damage.
The intracerebral gene therapy AMT-130 (AAV-microRNA) has shown in interim data a possible slowing of progression: it would be the first signal of a therapy acting on the cause. Still under evaluation.
Establishing MSH3 and other repair genes as drivers of somatic expansion opens a different strategy: stopping the growth of the CAG before neurons reach the toxic threshold.
Relying on biomarkers such as NfL to detect early damage, the goal is to intervene years before the symptoms appear.
Allele-selective therapies and base editing or prime editing that correct or switch off the expanded allele while sparing the healthy copy of the gene.
Combining HTT silencing, slowing somatic expansion and neuroprotection to multiply the effect on progression.
Research is advancing very fast and some of these results are preliminary: specific dates and data may change as the clinical trials mature.
The questions that come up most when learning about the genetics of Huntington's.
Milestones and scientific sources on which this page is based.
An educational synthesis page; not a primary clinical source. Some 2024–2025 results are preliminary and may change. For medical decisions, consult professionals and the official resources of Huntington's disease associations.
Six questions to check what you take away. It grades itself: click an answer and you'll instantly see whether you got it right, with the explanation.