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

Pathogenic Genotype (%): % of individuals predicted to be affected based on their genotype

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)

Huntingtin reduction results in altered nuclear structure and heterochromatic instability.

Jessica C,Barron, Sean T,Coady, Abigayle C,Fleming, Samantha J,Carew, Makenna C A,Taylor, Emily P,Hurley, Firoozeh,Nafar, Matthew P,Parsons

Human molecular genetics · 2025-08-01

pmid:40748251

Along-Tract Diffusion Alterations in the Dentato-Rubro-Thalamic Tract Correlate With Motor and Cognitive Decline in Huntington's Disease.

Zexi,Wang, Alexia,Solomon, Janine M,Lupo, Jingwen,Yao

Human brain mapping · 2025-08-01

pmid:40748199

Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing.

Eleonora,Sabetta, Karin,Rallmann, Jonas,Bergquist, Pille,Taba, Abigail L,Pfaff, Bal Hari,Poudel, Davide,Ferrari, Massimo,Locatelli, Sulev,Kõks

Experimental biology and medicine (Maywood, N.J.) · 2025-07-17

pmid:40746751

Probing How Anti-huntingtin Antibodies Bind the Fibrillar Fuzzy Coat Using Solid-State NMR.

Raffaella,Parlato, Greeshma,Jain, Alessia,Lasorsa, Patrick C A,van der Wel

Chemistry (Weinheim an der Bergstrasse, Germany) · 2025-07-24

pmid:40702881

Dysregulation of huntingtin interacting protein networks in human juvenile Huntington's disease brain.

Sonia,Podvin, Brin,Rosenthal, Charles,Mosier, Enlin,Wei, Kathleen M,Fisch, Vivian,Hook

Journal of Huntington's disease · 2025-07-23

pmid:40702852

Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntington's disease pathogenesis in mice.

Jillian,Belgrad, Ashley,Summers, Christian,Landles, Jonathan R,Greene, Samuel,Hildebrand, Emily,Knox, Ellen,Sapp, Nozomi,Yamada, Raymond,Furgal, Rachael,Miller, Georgina F,Osborne, Kathryn,Chase, Eric,Luu, Jason,Freedman, Brianna,Bramato, Nicholas,McHugh, Vicky,Benoit, Daniel,O'Reilly, Paul,Greer, Gillian P,Bates, Thomas F,Vogt, Ramee,Lee, David,Howland, Marian,DiFiglia, Neil,Aronin, Anastasia,Khvorova

bioRxiv : the preprint server for biology · 2025-06-25

pmid:40667291

Ayurvedic Management of Rare Genetic Condition-Huntington's Chorea: A Case Report.

Mahesh,Sharma, Sourabh,Deshmukh, Trupti,Thakre, Rohit,Waskar, Nitika,Senger

Alternative therapies in health and medicine · 2025-07-15

pmid:40662609

From Brain to Blood: Uncovering Potential Therapeutical Targets and Biomarkers for Huntington's Disease Using an Integrative RNA-Seq Analytical Platform (BDASeq

João Rafael,Dias Pinto, Benedito,Faustinoni Neto, Luciana,Munhoz, Irina,Kerkis, Rodrigo Pinheiro,Araldi

Cells · 2025-06-25

pmid:40643497

The Role of Animal Models in Huntington's Disease Clinical Trials: Decoding Genetic, Non-Genetic, and Molecular Pathways.

Aarti A,Bhimanwar, Aditi S,Kulkarni, Virendra S,Gomase

Reviews on recent clinical trials · 2025-07-07

pmid:40626527