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 (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. Undiagnosed carriers of premutation and pathogenic HTT expansions, exhibit reduced striatal brain volumes and elevated neurofilament light chain levels before clinical diagnosis, consistent with findings observed across other loci¹³.

Mechanism

GoF/LoF

While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial¹⁴. 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 populations¹⁵.

Year

1993¹⁶

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

CAG

Pathogenic (ref.)

CAG

Pathogenic (gene)

AGC

Interruption (ref.)

CAA

Interruption (gene)

AAC

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

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

Population-scale repeat expansions elucidate disease risk and brain atrophy.

Vijay Kumar,Pounraja, Jae Hoon,Sul, Joseph,Herman, Sean,O'Keeffe, Veera,Rajagopal, Xiaodong,Bai, Michael D,Kessler, Neelroop,Parikshak, Karl,Landheer, Xingmin,Zhang, Sean,Yu, Lance,Zhang, Michelle G,LeBlanc, Jennifer,Rico-Varela, Frederic,Grau, Sarah,Wolf, Sriramkumar,Sundaramoorthy, Farshid,Sepehrband, Eli A,Stahl, Yuda,Huo, Mohsin,Ahmed, Susan,Croll, William,Salerno, John D,Overton, Jonathan,Marchini, Jeffrey,Reid, Luca A,Lotta, Aris,Baras, Goncalo R,Abecasis, Giovanni,Coppola, Sahar,Gelfman

Nature · 2026-04-08

pmid:41951733

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

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)

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

Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort.

Zakhiriddin,Khojakulov, Robin J,Palvadeau, Müge,Kovancılar-Koç, Irmak,Atay, Irmak,Şahbaz, Şeyma,Tekgül, Ayça,Şahin, Esmer Zeynep Duru,Badakal, Tuğçe,Gül-Demirkale, Vildan,Çiftçi, Elif,Bayraktar, Ceren,Tunca, Natalia,Smolina, Fulya,Akçimen, Ayşe Nazlı,Başak

International journal of molecular sciences · 2026-05-13

pmid:42196324

DNA methylation profiling in Huntington's disease reveals disease associated changes in the striatum.

Gregory,Wheildon, Adam R,Smith, Luke,Weymouth, Joshua,Harvey, Morteza,Kouhsar, Lachlan F,MacBean, Claire,Troakes, Ehsan,Pishva, Rebecca G,Smith, Katie,Lunnon

Clinical epigenetics · 2026-05-26

pmid:42185880

The pathological Huntingtin CAG triplet expansion differentially affects the diagnosis of systemic and organ-specific autoimmune diseases.

Moritz,Heyd, G Bernhard,Landwehrmeyer, Jan,Lewerenz

Frontiers in immunology · 2026-05-08

pmid:42183198

C57BL/6 BAC-CAG Huntington's disease mice show somatic CAG expansion and responses to small interfering RNAs comparable to the FVB strain.

Jillian,Belgrad, Ashley,Summers, Samuel,Hildebrand, Ellen,Sapp, Eric,Luu, Nozomi,Yamada, Dan,O'Reilly, Thomas F,Vogt, David,Howland, X William,Yang, Marian,DiFiglia, Neil,Aronin, Anastasia,Khvorova

bioRxiv : the preprint server for biology · 2026-05-12

pmid:42182232

Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment.

Emily N P,Prowse, Brooke A,Turkalj, Muriel,Sébastien, Lale,Gursu, Daniel,Beaudet, Jia,Feng, Chengqian,Zhou, Heidi M,McBride, Gary J,Brouhard, Mahmoud A,Pouladi, Adam G,Hendricks

iScience · 2026-04-17

pmid:42181265

Understanding Huntington's Disease: Epidemiology, Mechanisms, and Modeling Approaches.

Satya,Prakash, Neha,Kumari, Lovedeep,Singh, Kamal,Shah, Hitesh Kumar,Dewangan, Deepika,Bhatia

CNS & neurological disorders drug targets · 2026-05-11

pmid:42152675

Induced pluripotent stem cells from a transgenic minipig model of Huntington's disease reveal early metabolic changes.

Irena,Rysankova, David,Sekac, Hana,Hansikova, Katerina Vodickova,Kepkova, Petr,Vodicka, Michaela,Vaskovicova, Marie,Altmanova, Stefan,Juhas, Jana,Juhasova, Eliska,Taborska, Jiri,Klempir, Jan,Motlik, Jiri,Klima, Lars,Eide, Zdenka,Ellederova

Disease models & mechanisms · 2026-05-11

pmid:42109206