Huntington's Disease

About this condition

Huntington's disease is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, which encodes the huntingtin protein. Approximately 2.7 per 100,000 people worldwide carry the mutation, with higher prevalence in populations of European descent (10.6–13.7 per 100,000). The disease is characterized by motor symptoms (chorea, dystonia, parkinsonism), progressive cognitive decline, and psychiatric manifestations (depression, irritability, psychosis). Inheritance is autosomal dominant with essentially complete penetrance for repeat expansions of 40 or more CAG repeats. The disease is uniformly progressive and fatal, with mean survival of 15–20 years from symptom onset.

Normal HTT alleles contain 10–26 CAG repeats; 27–35 repeats are classified as intermediate (meiotically unstable but not disease-causing); 36–39 repeats show reduced penetrance; ≥40 repeats are fully penetrant and cause disease. Age of onset has an inverse correlation with repeat length: mean age of onset is 35–44 years overall, but longer repeats produce earlier onset. Juvenile Huntington's disease (onset before age 20, typically with ≥60 repeats) accounts for 5–10% of cases. Paternal transmission is associated with greater repeat expansion due to meiotic instability during spermatogenesis, explaining why juvenile-onset disease is typically paternally inherited.

Huntington's predictive testing is one of the most consequential genetic tests in medicine — at ≥40 repeats, the result is fully penetrant and definitive. A positive test enables psychological preparation, life planning including financial and legal decisions, enrollment in disease-modifying clinical trials (antisense oligonucleotides targeting mutant HTT are in advanced stages), reproductive counseling with options like preimplantation genetic testing, and informed decision-making. A negative result provides definitive relief and eliminates the need for surveillance. At-risk family members can now be tested with appropriate genetic counseling support.

Gene locus: HTT (4p16.3) — CAG trinucleotide repeat

Standard CAG repeat assays are accurate, but WGS with specialized repeat analysis provides precise sizing and detects somatic variability.

Precise repeat sizing matters — especially in the critical ranges

Huntington's testing is nominally straightforward — a CAG repeat assay is well-established. However, standard short-read sequencing panels and some WGS pipelines may not accurately size CAG repeats, particularly in the intermediate and reduced-penetrance ranges where precise counts have enormous clinical implications. The difference between 35 repeats (no disease) and 40 repeats (certain disease) is decisive. Somatic mosaicism in repeat length across tissues is now recognized as clinically relevant but not captured by blood-based testing alone. Long-read WGS capability or specialized repeat analysis can provide precise repeat sizing, detect somatic instability, and identify modifier variants in other genes (DNA repair genes) that influence age of onset.

Knowing your status enables preventive clinical trials and life planning

A positive Huntington's test is definitive — at ≥40 repeats, disease is essentially certain. That definitiveness enables people to pursue previously unavailable options: enrollment in disease-modifying clinical trials (antisense oligonucleotides like tominersen are in advanced development), reproductive counseling with preimplantation genetic testing (PGT-M) to prevent transmission, financial and legal planning while cognitive function remains intact, and psychological preparation with appropriate support. A negative result provides definitive reassurance. Family members can be tested with confidence in the result.

You've lived with a coin-flip question since childhood. It takes courage to ask for the answer — and the answer changes everything.