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)

Short tandem repeat expansions in patients with neurodegenerative dementia.

Yuan,Zhu, Xuewen,Xiao, Yiliang,Liu, Zheng,Wang, Tengfei,Luo, Tianyan,Xu, Qijie,Yang, Xiaoli,Hao, Cong,Zhang, Sizhe,Zhang, Shilin,Luo, Yafang,Zhou, Xinxin,Liao, Yun,Tian, Ling,Weng, Liangjuan,Fang, Beisha,Tang, Bin,Jiao, Jinchen,Li, Lu,Shen

EBioMedicine · 2026-02-26

pmid:41762523

Silmitasertib, an FDA-designated orphan CK2 inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model.

Ross J,Pelzel, Miaya,Herbst, Nicholas B,Rozema, Melissa A,Solem, Rocio,Gomez-Pastor

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026-02-24

pmid:41741274

Pediatric-onset spinocerebellar ataxia type 3 with dual

Dedong,Wang, Mengyao,Zhou, Kang,Du, Yue,Wang, Kunzhi,Tang, Yuanfang,Duan, Mengting,Shi, Haohao,Wu

Frontiers in genetics · 2026-02-10

pmid:41736717

The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.

Sanaz,Gabery, Sofia,Bergh, Chrisovalantou,Huridou, Rachel Y,Cheong, Barbara,Baldo, Paul Günther,Scheunemann, Marie-Louisa,Schoebel, Linda Holmquist,Mengelbier, Elisabet,Englund, Catriona,McLean, Carsten,Saft, Deniz,Kirik, Maria,Björkqvist, Glenda,Halliday, Elisabeth,Petrasch-Parwez, Huu Phuc,Nguyen, Jonasz Jeremiasz,Weber, Åsa,Petersén

Brain pathology (Zurich, Switzerland) · 2026-02-24

pmid:41736445

The NeuroBioBank whole-genome catalogue of human brain donors with central nervous system disorders.

Daniel,Hupalo, Jacob L,McCauley, Lissette,Gomez, Anthony J,Griswold, Gabriela,Hoher, Ioanna,Konidari, Jose,Lorenzo, Griffin S,Parker, Julianna,Pascual, Amanda R,Sandford, Patrice L,Whitehead, David A,Davis, Susanna,Garamszegi, S Humayun,Gultekin, Xiaoyan,Sun, Regina T,Vontell, Michael,Chatigny, Darren,Chernicky, Myrtha M,Constant, Isabelle G,Darling, David J,Ennulat, John M,Esposito, Kiely,Morris, Elisabeth S,Lawton, Neda R,Morakabati, Phyllis,Oduor, Allison P,Rodgers, Lorelle A,Sang, Kathleen M,Sullivan, Catalina J,Tabit, Tori,Turpin, Aya,Zeabi, Tina,Zheng, Sabina,Berretta, Torsten,Klengel, W Brad,Ruzicka, Derek H,Oakley, Thomas,Blanchard, Eric,Ho, Robert,Johnson, Alexandra,LeFevre, Maxwell,Bustamante, Vahram,Haroutunian, Christine,Marino, Dushyant P,Purohit, Michael,Wysocki, Jill R,Glausier, David A,Lewis, Rashed M,Nagra, Camille,Alba, Julianna,Martin, Elizabeth,Rice, John,Rosenberger, Grace,Smith, Gauthaman,Sukumar, Miranda,Tompkins, Matthew D,Wilkerson, Clifton L,Dalgard, William K,Scott

Brain : a journal of neurology · 2026-02-16

pmid:41697960

Diagnostic yield of genome sequencing in children with progressive movement disorders.

Luca,Schierbaum, Enrique,Gonzalez Saez-Diez, Amy,Tam, Joshua,Rong, Umar,Zubair, Katerina,Bernardi, Kathryn,Yang, Vicente,Quiroz, Zainab,Zaman, Afshin,Saffari, Siofra,Carty, Habibah A P,Agianda, Sanda,Alexandrescu, Florian,Eichler, Abigail,Sveden, Maya,Chopra, Daniel G,Calame, Matt C,Danzi, Stephan,Zuchner, Darius,Ebrahimi-Fakhari

Brain : a journal of neurology · 2026-02-05

pmid:41640354

The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease.

Aikaterini Smaragdi,Papadopoulou, Christian,Landles, Edward J,Smith, Marie K,Bondulich, Annett,Boeddrich, Maria,Canibano-Pico, Emily C E,Danby, Franziska,Hoschek, Arzo,Iqbal, Samuel T,Jones, Nancy,Neuendorf, Iulia M,Nita, Georgina F,Osborne, Jemima,Phillips, Maximilian,Wagner, Erich E,Wanker, Jonathan R,Greene, Andreas,Neueder, Gillian P,Bates

Brain : a journal of neurology · 2026-02-02

pmid:41622913

pmid:41620818

Non-Huntington's disease chorea: an expanding universe with acquired causes.

Francisco,Cardoso, Débora,Maia, Ricardo,Maciel, Jonathan,Carr, Taku,Hatano, Alexandra,Durr, Werner,Poewe

Brain : a journal of neurology · 2026-01-30

pmid:41612618