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

Typical: 35-44³; Range: 1-85^4,5.

HPO Terms

HP:0000496 Abnormality of eye movement HP:0000657 Oculomotor apraxia HP:0000713 Agitation HP:0000716 Depression HP:0000718 Aggressive behavior HP:0000722 Compulsive behaviors HP:0000726 Dementia HP:0000734 Disinhibition HP:0000737 Irritability HP:0000738 Hallucinations HP:0000739 Anxiety HP:0000741 Apathy HP:0000746 Delusion HP:0000751 Personality changes HP:0001250 Seizure HP:0001262 Excessive daytime somnolence HP:0001268 Mental deterioration HP:0001272 Cerebellar atrophy HP:0001288 Gait disturbance HP:0001332 Dystonia HP:0001336 Myoclonus HP:0001347 Hyperreflexia HP:0001824 Weight loss HP:0002059 Cerebral atrophy HP:0002063 Rigidity HP:0002066 Gait ataxia HP:0002067 Bradykinesia HP:0002072 Chorea HP:0002141 Gait imbalance HP:0002169 Clonus HP:0002171 Gliosis HP:0002300 Mutism HP:0002312 Clumsiness HP:0002340 Caudate atrophy HP:0002354 Memory impairment HP:0002375 Hypokinesia HP:0002500 Abnormal cerebral white matter morphology HP:0002529 Neuronal loss in central nervous system HP:0002540 Inability to walk HP:0002591 Polyphagia HP:0003107 Abnormal circulating cholesterol concentration HP:0003324 Generalized muscle weakness HP:0003487 Babinski sign HP:0004305 Involuntary movements HP:0004408 Abnormality of the sense of smell HP:0007010 Poor fine motor coordination HP:0009088 Speech articulation difficulties HP:0010794 Impaired visuospatial constructive cognition HP:0025401 Staring gaze HP:0030842 Choking episodes HP:0030955 Addictive alcohol use HP:0031473 Anger HP:0031589 Suicidal ideation HP:0031843 Abnormally slow thought process HP:0031845 Abnormal libido HP:0040140 Degeneration of the striatum HP:0045082 Decreased body mass index HP:0100785 Insomnia HP:0200136 Oral-pharyngeal dysphagia

Association

MendelianRisk

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 (CAA)^7,8. Only fathers with premutations are considered at risk of transmitting pathogenic alleles⁹. CAG repeat size 21-35 may continuously modulate brain structure and psychiatric disease risk in an age-dependent manner^6,10. Somatic expansion of HTT CAG repeats in vulnerable tissues is proposed to contribute to age-dependent onset and neurodegeneration, with greater repeat instability associated with earlier disease onset^11,12. A GWAS of residual age at motor onset after accounting for CAG length in ~9,000 individuals of European ancestry identified modifier loci whose candidate genes function in DNA maintenance (FAN1, MSH3, MLH1, PMS1, PMS2, LIG1); these are modifiers of onset timing, most likely acting through an effect on somatic expansion¹³. Knockout studies in HD mouse models separately established that Msh2, Msh3, Mlh1, and Mlh3 were required for somatic CAG expansion¹⁴.

Mechanism

GoF/LoF

While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial¹⁵. Somatic expansion and age of onset are modified by trans acting DNA repair gene variants^13,16. Reduced SCN4B expression in striatal neurons has been implicated as a modifier of HD-associated phenotype severity, potentially contributing to dysfunction in motor associated striatal neuronal populations¹⁷.

Detection

PCR methods have reliably detected expansions up to ~115 repeats, but very large expansions may require Southern blotting³. Long-read sequencing has resolved interruptions and validated sizing¹⁸.

Year

1993¹⁹

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

CAG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CAG

Pathogen. (gene)

CAG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

CAA

Interrup. (gene)

CAA

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

3genereviews: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

When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington's disease.

Elena,Cattaneo, Davide,Scalzo, Martina,Zobel, Raffaele,Iennaco, Camilla,Maffezzini, Dario,Besusso, Simone,Maestri

Nucleic acids research · 2025-01-07

pmid:39673793

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

Huntingtin CAG repeat is a continuous modifier of brain structure and health vulnerability

Harriet,Cullen, Christopher,Clarkson, Henrique,Nascimento, Matteo,Zanovello, Jeffrey,Long, Mark,Caulfield, Michael,Simpson, Sarah J,Tabrizi, Arianna,Tucci

Genetic and Genomic Medicine · 2026-05-12

doi:https://doi.org/10.64898/2026.05.08.26352223

Extensive transcriptomic changes in cellular and animal models of Huntington's disease depending on the length of CAG repeats in the exon 1 of the HTT gene.

Aneta,Szulc, Beata M,Walter, Lidia,Gaffke, Karolina,Wiśniewska, Magdalena,Żabińska, Estera,Rintz, Zuzanna,Cyske, Michał,Grabski, Oleksandr,Pankiv, Magdalena,Podlacha, Karolina,Pierzynowska, Grzegorz,Węgrzyn

Biochemical and biophysical research communications · 2026-04-01

pmid:41926793

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease.

Robert E,Handsaker, Seva,Kashin, Nora M,Reed, Steven,Tan, Won-Seok,Lee, Tara M,McDonald, Kiely,Morris, Nolan,Kamitaki, Christopher D,Mullally, Neda R,Morakabati, Melissa,Goldman, Gabriel,Lind, Rhea,Kohli, Elisabeth,Lawton, Marina,Hogan, Kiku,Ichihara, Sabina,Berretta, Steven A,McCarroll

Cell · 2025-01-16

pmid:39824182

CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset.

Cell · 2019-08-08

pmid:31398342

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models.

Vanessa C,Wheeler, Vincent,Dion

Journal of Huntington's disease · 2021-01-01

pmid:33579861

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

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects.

Nature genetics · 2025-06-09

pmid:40490511

Scn4b Modulates Huntington's Disease Phenotype Severity in vivo.

Suphinya,Sathitloetsakun, Vanessa,Farrell, S Sebastian,Pineda, Hyeseung,Lee, Jung Hoon,Shin, Francisco J,Garcia, Raleigh M,Linville, Manolis,Kellis, Veronica A,Alvarez, Myriam,Heiman

bioRxiv : the preprint server for biology · 2026-03-10

pmid:41959367

18pmid:41512049

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)

Revisiting the Link Between Huntington's Disease and Cancer: Evidence from the Enroll-HD dataset.

Natalia,Rocha, Jack,Ringold, Karina Lucia,Moreira Sassi, Eunyoung,Lee, Emily,Tharp, Shivika,Chandra, Erin,Furr Stimming

Neuroepidemiology · 2026-07-30

pmid:42531186

Emotion regulation across disease stages in Huntington's disease gene expansion carriers.

Emilie,Poulsen, Birna,Ásbjörnsdóttir, Lena E,Hjermind, Jørgen E,Nielsen, Asmus,Vogel

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists · 2026-05-29

pmid:42467959

xHD-Vox, an Automated Speech Model for Estimating Motor and Cognitive Scores in Huntington Disease: Development and Longitudinal Validation.

Tiphaine,Le Ludec, Andres,Gil-Salcedo, Hadrien,Titeux, Robin,Louiset, Clément,Le Moine Veillon, Renaud,Massart, Anne-Catherine,Bachoud-Lévi

JMIR neurotechnology · 2026-07-08

pmid:42422859

Repeat expansions in Parkinson's disease and parkinsonism across ancestries: insights from a global genetic cohort.

Lara M,Lange, Catalina,Cerquera-Cleves, Ai Huey,Tan, Shen-Yang,Lim, Njideka U,Okubadejo, Chin-Hsien,Lin, Pin-Shiuan,Chen, Jung Hwan,Shin, Azlina,Ahmad-Annuar, Laurel A,Screven, Viorica,Chelban, Allison A,Dilliot, André,Fienemann, Kamalini Ghosh,Galvelis, Henry,Houlden, Hirotaka,Iwaki, Zane,Jaunmuktane, Patrick W,Cullinane, Thomas,Warner, Johanna,Junker, Yuliia,Kanana, Ignacio J Keller,Sarmiento, Christine,Klein, Pin-Jui,Kung, Hampton L,Leonard, Niccoló E,Mencacci, Mike A,Nalls, Raquel,Real, Samia Ben,Sassi, Joanne,Trinh, Dan,Vitale, Ana,Westenberger, Lesley Y,Wu, Andrew B,Singleton, Huw R,Morris, Katja,Lohmann, Cornelis,Blauwendraat, Peter,Heutink, Zih-Hua,Fang

medRxiv : the preprint server for health sciences · 2026-06-22

pmid:42396269

WWOX contributes to DNA damage, but not somatic instability in Huntington's disease.

Tiziana,Petrozziello, Zachariah L,McLean, Adel,Boudi, Sommer S,Huntress, Eric J,Granucci, Grace A,Field, Ranee Zara B,Monsanto, Ayleen L,Castillo Torres, Jennie C L,Roy, Maheswaran,Kesavan, Muzhou,Wu, Neil,Doherty, Ellen,Sapp, Mahmoud A,Pouladi, Kimberly B,Kegel-Gleason, Marian,DiFiglia, James F,Gusella, Ricardo,Mouro Pinto, Ghazaleh,Sadri-Vakili

bioRxiv : the preprint server for biology · 2026-06-26

pmid:42395553

Mismatch repair dissection by in vivo RNAi reveals dose-dependent modulators of somatic instability and proteome remodeling in Huntington's disease.

Jillian,Belgrad, Todd M,Greco, Ellen,Sapp, Ashley,Summers, Daniel,O'Reilly, Eric,Luu, Josiah E,Hutton, Nozomi,Yamada, Hassan H,Fakih, Raymond,Furgal, Dimas,Echeverria, Nicholas,McHugh, Brianna,Bramato, Chantal,Furguson, Samuel,Hildebrand, Sarah,Allen, Nicholas,Gaston, David,Cooper, Allison,Maebius, Katherine Y,Gross, Thomas F,Vogt, Michael,Finley, Brinda,Prasad, Marian,DiFiglia, Ileana M,Cristea, Neil,Aronin, Anastasia,Khvorova

bioRxiv : the preprint server for biology · 2026-06-24

pmid:42395360

A Multi-Regional Single-nucleus Atlas of the Huntington's Disease Brain.

Jiawei,Li, Qin,Zhou, Chunxiang,Shi, Yingqi,Lin, Bofeng,Han, Jiale,Gao, Jiacheng,Li, Caijuan,Li, Yizhi,Chen, Chunhui,Huang, Jianhao,Wu, Wei,Wang, Junzhu,Song, Yuanpei,Zhang, Qingqing,He, Wentai,Wang, Zhuchi,Tu, Shihua,Li, Xiao-Jiang,Li, Bo,Ning, Sen,Yan

Scientific data · 2026-07-02

pmid:42393093

CD11c

Silvia,D'Orso, Francesca,La Gualana, Anthony,Vignone, Silvia,Acati, Francesca,Oliva, Annalisa,Villa, Francesca,Maiorca, Milvia,Casato, Lucia,Stefanini, Silvia,Piconese, Marcelo,Teocchi, Giovanna,Borsellino, Stefania,Basili, Domenico,Alvaro, Marcella,Visentini, Vincenzo,Cardinale

Liver international : official journal of the International Association for the Study of the Liver · 2026-08-01

pmid:42385197

Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease.

Miguel,da Silva Padilha, Seda,Koyuncu, Evangeline,Chabanis, Sergey,Ryazanov, Andrei,Leonov, David,Vilchez, Rüdiger,Klein, Armin,Giese, Christian,Griesinger, Irina,Dudanova

EMBO molecular medicine · 2026-06-26

pmid:42362792

Locus HD HTT

Disease

Locus

Alleles

gnomAD

References

Additional Literature