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

–

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 manner⁶¹⁰. 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.

Mechanism

GoF/LoF

While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial¹³. Somatic expansion and age of onset are modified by trans acting DNA repair gene variants^14,15. Mismatch repair genes (MSH3, MLH1, MLH3, PMS1, and PMS2) promote expansion¹⁶, while the nuclease FAN1 stabilizes the repeat¹⁷. 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 populations¹⁸.

Detection

PCR methods have reliably detected expansions up to ~115 repeats, but very large expansions may require Southern blotting [@genereviews:NBK1305]. Long-read sequencing has resolved interruptions and validated sizing [@pmid:41512049].

Year

1993¹⁹

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

CAG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CAG

Pathogenic (gene)

CAG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

CAA

Interruption (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

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

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

Cell · 2019-08-08

pmid:31398342

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

16pmid:24204323

FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.

Robert,Goold, Michael,Flower, Davina Hensman,Moss, Chris,Medway, Alison,Wood-Kaczmar, Ralph,Andre, Pamela,Farshim, Gill P,Bates, Peter,Holmans, Lesley,Jones, Sarah J,Tabrizi

Human molecular genetics · 2019-02-15

pmid:30358836

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

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)

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

Somatic CRISPR editing of

Esaria,Oliver, Marina,Kovalenko, Mathilde,Louçã, Andrew,Jiang, Jordan,Westerdahl, Kevin,Correia, Benjamin,Jones, Faaiza,Saif, Nicole,Romano, Ashna,Sidhu, Tammy,Gillis, Emanuela,Elezi, Ryan,Murtha, Ricardo Mouro,Pinto, Vanessa C,Wheeler

bioRxiv : the preprint server for biology · 2026-06-10

pmid:42327018

Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion.

Rob,Goold, Jasmine,Donaldson, Florence,Gidney, Philip,Goff, Joseph,Hamilton, Marwa,Elmasri, Lucy,Coupland, Michael,Flower, Sarah J,Tabrizi

NAR molecular medicine · 2026-06-05

pmid:42317610

The genetic landscape of childhood-onset dystonia in a nationwide Turkish cohort: Clinical spectrum, molecular diagnostics, and therapeutic implications.

Sanem,Yilmaz, Esra,Serdaroglu, Erdem,Simsek, Bulent,Kara, Dilsad,Turkdogan, Uluc,Yis, Ilknur,Erol, Deniz,Yuksel, Seda,Kanmaz, Arzu,Eroglu, Mehmet,Canpolat, Mustafa,Komur, Nese,Cıtak Kurt, Ayfer,Sakarya Gunes, Didem,Soydemir, Seyda,Besen, Omer,Bektas, Serkan,Kirik, Hale,Atalay Celik, Didem,Ardicli, Ayse,Aksoy, Coskun,Yarar, Cisil,Cerci Kubur, Nihal,Olgac Dundar, Olcay,Gungor, Tulay,Kamasak, Cemile Busra,Olculu, Hakan,Gumus, Mirac,Yildirim, Esra,Isik, Tahir,Atik, Ozgur,Cogulu, Ayse Nazli,Basak, Deniz,Sunnetci Akkoyunlu, Derya Hazal,Özbakır, Gülsüm,Kayhan, Hamide Betul,Gerik Çelebi, Kadri,Karaer, Munis,Dundar, Rauan,Kaiyrzhanov, Serdar,Ceylaner, Huseyin,Per, Ayse Semra,Hiz, Ali,Cansu, Cetin,Okuyaz, Banu,Anlar, Hasan,Tekgul

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society · 2026-06-16

pmid:42308683

Defective B cell tolerance in SLE lymph nodes underpins VH

Caterina E,Faliti, Midushi,Ghimire, Melissa,Garcia-Vega, Rachel C,Watermeier, Amanda,Callahan, Julia,Burke, Olivia,Posadas, Ashish K,Mishra, Surender,Khurana, Victor,Greiff, Chris D,Scharer, John M,Lindner, R Glenn,King, Mary,Newell, Arezou,Khosroshahi, F Eun-Hyung,Lee, Iñaki,Sanz

medRxiv : the preprint server for health sciences · 2026-05-18

pmid:42238417

Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons.

Lea,Danics, Chandramouli,Muralidharan, Ágnes,Varga, Melinda,Rezeli, Jeovanis,Gil, Anna A,Abbas, Ádám,Pap, Andrew S,Park, Marcell,Cserhalmi, Emilie M,Legault, Ármin,Sőth, Dorina,Jamniczky, Roland,Zsoldos, Roger A,Barker, Gergely,Róna, Janelle,Drouin-Ouellet, György,Markó-Varga, Zsuzsanna,Darula, Karolina,Pircs

Cellular & molecular biology letters · 2026-06-02

pmid:42231151

Temporal single-cell atlas of full-length Huntington's disease mouse model defines stage-specific signatures of corticostriatal dysfunction.

Ashley B,Robbins, Paul T,Ranum, Icnelia,Huerta-Ocampo, Michael,Kuckyr, Beverly L,Davidson

Molecular neurodegeneration · 2026-05-28

pmid:42210302

Clinical implications of loss of interruption variants for diagnosis, genetic counselling, and clinical trials in Huntington's disease.

Hailey,Findlay Black, Jessica,Levesley, Chris,Kay, Stephanie,Bortnick, Kyla,Javier, Michael R,Hayden

Journal of Huntington's disease · 2026-05-27

pmid:42202221

Locus HD HTT

Disease

Locus

Alleles

gnomAD

References

Additional Literature