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 manner⁶. 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^10,11. 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 loci¹².

Mechanism

GoF/LoF

While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial¹³. 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 populations¹⁴.

Year

1993¹⁵

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

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)

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

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

Towards AI-driven prediction of

Simone,Maestri, Davide,Scalzo, Martina,Zobel, Dario,Besusso, Elena,Cattaneo

Journal of Huntington's disease · 2026-04-20

pmid:42007924

Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions.

Fulya,Akçimen, Monica,Diez-Fairen, Ignacio,Alvarez, Victor,Puente, Spencer,Grant, Jorge,Hernandez-Vara, Marzieh,Khani, Mariateresa,Buongiorno, Félix Javier,Jiménez-Jiménez, José A G,Agúndez, Miquel,Aguilar, Esther,Cubo, Jesus,Perez, Javier,Pagonabarraga, Núria,Caballol, Asuncion,Avila, Jinhui,Ding, Elena,García-Martín, Hortensia,Alonso-Navarro, Yaroslau,Compta, Carlos,Cruchaga, Katrin,Beyer, J Raphael,Gibbs, Andrew,Singleton, Sara,Bandres-Ciga, Pau,Pastor

NPJ genomic medicine · 2026-04-09

pmid:41957010

Pyramidal signs in Huntington's disease: An early clinical indicator associated with proximity to disease onset.

Xiao-Yan,Li, Yu-Feng,Bao, Chen-Chang,Hu, Yi,Dong, Zhi-Ying,Wu

Med (New York, N.Y.) · 2026-03-30

pmid:41916314

Inhibition of the NLRP3 Inflammasome With MCC950 Improves Gut Health in Huntington's Disease Mice.

Sujan Kumar,Sarkar, Millicent N,Ekwudo, Da,Lu, Bethany,Masson, Pamudika,Kiridena, Nicholas,van de Garde, Thibault,Renoir, James E,Vince, Veerasikku Gopal,Deepagan, Anthony J,Hannan, Carolina,Gubert

Journal of neurochemistry · 2026-04-01

pmid:41906693

Aberrant expression of the MID1 protein in neurons of Huntington's disease brain.

Adriana,Geraci, Annika,Reisbitzer, Janina,Gerhard, Sybille,Krauß

Frontiers in genetics · 2026-03-11

pmid:41884622