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

chr4:3076604-3076667

hg38

chr4:3074877-3074940

t2t

chr4:3073604-3073694

Details

27-35 motifs are unstable/premutations, while 36-39 motifs are associated with reduced penetrance and mild phenotypes⁶. >60 motifs assocated 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

Exon 1

Gene Strand

Alleles

Ref. Motif

CAG

Pathogenic (ref.)

CAG

Pathogenic (gene)

AGC

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

Huntington Disease

Nicholas S.,Caron, Galen EB,Wright, Michael R.,Hayden

GeneReviews® · 1993-01-01

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)

Mutant huntingtin protein decreases with CAG repeat expansion: implications for therapeutics and bioassays.

Christian,Landles, Georgina F,Osborne, Jemima,Phillips, Maria,Canibano-Pico, Iulia M,Nita, Nadira,Ali, Konstantin,Bobkov, Jonathan R,Greene, Kirupa,Sathasivam, Gillian P,Bates

Brain communications · 2024-11-15

pmid:39713241

Navigating triplet repeats sequencing: concepts, methodological challenges and perspective for Huntington's disease.

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

Nucleic acids research · 2024-12-16

pmid:39676657

Ascertainment of uninterrupted CAG repeat length and disease-modifying variants in fragment-based genetic testing for Huntington Disease.

Hailey,Findlay Black, Chris,Kay, Jessica,Dawson, Stephanie,Bortnick, Kyla,Javier, Qingwen,Xia, Cheuk Hin,Chau, Tess,Leavitt, Larissa,Arning, Huu Phuc,Nguyen, Michael R,Hayden

Genetics in medicine open · 2024-08-02

pmid:39669608

Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.

Milan,Zimmermann, David,Mengel, Katrin,Raupach, Tobias,Haack, Manuela,Neumann, Matthis,Synofzik

Journal of neurology · 2024-12-12

pmid:39666103

Distinct roles of ascorbic acid in extracellular vesicles and free form: Implications for metabolism and oxidative stress in presymptomatic Huntington's disease.

Felipe A,Beltrán, Leandro,Torres-Díaz L, Paulina,Troncoso-Escudero, Juan,Villalobos-González, Gonzalo,Mayorga-Weber, Marcelo,Lara, Adriana,Covarrubias-Pinto, Sharin,Valdivia, Isidora,Vicencio, Eduardo,Papic, Carolina,Paredes-Martínez, Mara E,Silva-Januàrio, Alejandro,Rojas, Luis L P,daSilva, Felipe,Court, Abraham,Rosas-Arellano, Luis Federico,Bátiz, Patricio,Rojas, Francisco J,Rivera, Maite A,Castro

Free radical biology & medicine · 2024-12-09

pmid:39662690

Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants.

Margaux L A,Hujoel, Robert E,Handsaker, Nolan,Kamitaki, Ronen E,Mukamel, Simone,Rubinacci, Pier F,Palamara, Steven A,McCarroll, Po-Ru,Loh

bioRxiv : the preprint server for biology · 2024-11-26

pmid:39651202

CRISPR/Cas9-induced double-strand breaks in the huntingtin locus lead to CAG repeat contraction through DNA end resection and homology-mediated repair.

Pawel,Sledzinski, Mateusz,Nowaczyk, Marianna Iga,Smielowska, Marta,Olejniczak

BMC biology · 2024-12-03

pmid:39627841

β-Blocker Use and Delayed Onset and Progression of Huntington Disease.

Jordan L,Schultz, Amy C,Ogilvie, Lyndsay A,Harshman, Peg C,Nopoulos

JAMA neurology · 2024-12-02

pmid:39621338

How many people have a Huntington's Disease expansion: A population-based prevalence study in Northern Scotland.

Heather,Cruickshank, Zosia,Miedzybrodzka

Neuroepidemiology · 2024-11-29

pmid:39617003