HD HTT

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia¹.

Prevalence

1 10,000

6.5-15/100,000². 9.71-17:100,000 (European) vs. 0.1-2/100,000 (African), as many as 1 in 400 have reduced penetrance (0.2-2% for 36-38 CAG) HTT alleles³. Found across ethnicities/ancestries, with population-dependent prevalence³.

Age of Onset Details

Typical: 35-44³; Range: 1-85^4,5.

Locus

hg19

chr4:3076603-3076660

hg38

chr4:3074876-3074933

t2t

chr4:3073603-3073687

Details

27-35 motifs are unstable/premutations, while 36-39 motifs are associated with reduced penetrance and mild phenotypes⁶, and alleles over 40 repeats are typically fully penetrant³. >60 motifs associated with onset age <20 years³. Only CAG expansions are considered pathogenic, but interruptions impact pathogenicity (e.g. CAA)⁷. Only fathers with premutations are considered at risk of transmitting pathogenic alleles⁸. CAG repeats in the non-HD range (>= 21 repeats) may modulate psychiatric disease risk in an age-dependent manner⁶

Mechanism

GoF/LoF

While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial⁹.

Year

1993¹⁰

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

CAG

Pathogenic (ref.)

CAG

Pathogenic (gene)

AGC

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007739

Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.

Haibao,Tang, Ewen F,Kirkness, Christoph,Lippert, William H,Biggs, Martin,Fabani, Ernesto,Guzman, Smriti,Ramakrishnan, Victor,Lavrenko, Boyko,Kakaradov, Claire,Hou, Barry,Hicks, David,Heckerman, Franz J,Och, C Thomas,Caskey, J Craig,Venter, Amalio,Telenti

American journal of human genetics · 2017-11-02

pmid:29100084

genereviews:NBK1305

Expanding the Phenotype of Extremely Early Onset Juvenile Huntington's Disease: A Case Report and Review of Previously Published Cases.

Zöe,Powis, Jonathon,Lutz, Khalida,Liaquat, Jyes A,Querubin, Sat Dev,Batish

American journal of medical genetics. Part A · 2024-10-23

pmid:39441074

Huntington's disease: a clinical review.

Raymund A C,Roos

Orphanet journal of rare diseases · 2010-12-20

pmid:21171977

Huntingtin CAG repeat size variations below the Huntington's disease threshold: associations with depression, anxiety and basal ganglia structure.

Magdalena,Vater, Nicolas,Rost, Gertrud,Eckstein, Susann,Sauer, Alina,Tontsch, Angelika,Erhardt, Susanne,Lucae, Tanja,Brückl, Thomas,Klopstock, Philipp G,Sämann, Elisabeth B,Binder

European journal of human genetics : EJHG · 2024-11-21

pmid:39572770

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG).

Audrey E,Hendricks, Jeanne C,Latourelle, Kathryn L,Lunetta, L Adrienne,Cupples, Vanessa,Wheeler, Marcy E,MacDonald, James F,Gusella, Richard H,Myers

American journal of medical genetics. Part A · 2009-07-01

pmid:19507258

Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies.

Maria,Jimenez-Sanchez, Floriana,Licitra, Benjamin R,Underwood, David C,Rubinsztein

Cold Spring Harbor perspectives in medicine · 2017-07-05

pmid:27940602

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.

Cell · 1993-03-26

pmid:8458085

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Atrazine Induces Reproductive Toxicity in an

Monsikan,Chaiyakit, Rangsun,Parnpai, In K,Cho

Biomedicines · 2025-11-28

pmid:41462929

A shared DNA-repeat toxicity threshold, reached somatically at cell-type-specific rates, unites cortical and striatal neurodegeneration in Huntington's disease.

Seva,Kashin, Won-Seok,Lee, Tara M,McDonald, Kiely,Morris, Robert E,Handsaker, Curtis,Mello, Liv,Spina, Nora M,Reed, Heather,de Rivera, Sri Havya,Jana, Marina,Hogan, Sabina,Berretta, Steven A,McCarroll

bioRxiv : the preprint server for biology · 2025-12-11

pmid:41427302

The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis.

Joke J F A,van Vugt, Ramona A J,Zwamborn, Egor,Dolzhenko, Michael A,Eberle, Ben,Weisburd, Erwin,Bekema, Maarten,Kooyman, Bi-Nan,Wang, Erik-Jan,Kamsteeg, Monique,Losekoot, Frank,Baas, Camilla,Novy, Helle,Høyer, Ruben P A,van Eijk, Michael A,van Es, Wouter,van Rheenen, Ammar,Al-Chalabi, Leonard H,van den Berg, Jan H,Veldink

Brain communications · 2025-12-09

pmid:41426430

Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.

Hyeonho,Kim, Gaeun,Hyun, Seunghye,Kim, Changmo,Yu, Young-Gi,Hong, Jihyeon,Yu, Sangsu,Bae, Hyun-Woo,Rhee, Jaewon,Ko, Ji Won,Um

Theranostics · 2026-01-01

pmid:41424860

Sequence Variants in Small CAG Repeat Expansions of the

Anna,Heinzmann, Emilien,Petit, Jessica,Dawson, Chris,Kay, Claire-Sophie,Davoine, Jean-Loup,Méreaux, Hailey Findlay,Black, Larissa,Arning, Huu Phuc,Nguyen, Giulia,Coarelli, Sabrina,Sayah, Jeremie,Pariente, Fleur,Gérard, Hortense,Hurmic, Michael R,Hayden, Alexandra,Durr

Neurology · 2025-12-19

pmid:41418088

A human CAGinSTEM platform for decoding HTT repeats' somatic instability links CAG interruption to HD pathology in neurons.

Martina,Zobel, Gianluca,Damaggio, Maria Lidia,Mignogna, Dario,Besusso, Davide,Scalzo, Andrea,Cossu, Camilla,Trovesi, Mariacristina,Crosti, Francesco,Cortina, Ilaria,Campus, Giulio,Formenti, Saveria,Mazzara, Francesco,Gregoretti, Laura,Antonelli, Gennaro,Oliva, Chiara,Zuccato, Vincenza,Colonna, Paola,Conforti, Matteo,Cereda, Riccardo Lorenzo,Rossi, Simone,Maestri, Andrea,Scolz, Raffale,Iennaco, Elena,Cattaneo

Cell reports · 2025-12-11

pmid:41389205

The profiling of extracellular vesicle subtypes in Huntington's disease brains identifies Alix as a novel marker of neuropathology.

Rocío,Pérez-González, Anna,Vázquez-Oliver, Nil,Salvat-Rovira, Saül,Martínez-Horta, Elisa,Rivas-Asensio, Eva,Borràs, Samanta,Ortuño-Miquel, María,Sánchez-Carcelén, Marta,Garcia-Forn, Frederic,Sampedro, Jesús,Pérez-Pérez, Eduard,Sabidó, Esther,Pérez-Navarro, Jaime,Kulisevsky

Acta neuropathologica communications · 2025-12-08

pmid:41361856

Sex- and Depression-specific Effects of Non-pathogenic CAG Repeats in

Linjun,Ao, Raymond,Noordam, N,Ahmad Aziz, Yuri,Milaneschi, Diana,van Heemst, Frits R,Rosendaal, Brenda W J H,Penninx, Ko Willems,van Dijk, Tamar,Sofer, Heming,Wang, Tariq,Faquih

medRxiv : the preprint server for health sciences · 2025-11-27

pmid:41358280

Impaired nick recognition and ligation efficiency by LIG1 K845N variant linked to Huntington's disease.

Jacob,Ratcliffe, Camden E,Lerner, Kanal,Balu, Surajit,Chatterjee, Kar Men,Lee, Melike,Caglayan

NAR molecular medicine · 2025-10-28

pmid:41346861