A Worldwide Study of the Huntington's Disease Mutation: The Sensitivity and Specificity of Measuring CAG Repeats
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BACKGROUND: Huntington's disease is associated with an expanded sequence of CAG repeats in a gene on chromosome 4p16.3. However, neither the sensitivity of expanded CAG repeats in affected persons of different ethnic origins nor the specificity of such repeats for Huntington's disease as compared with other neuropsychiatric disorders has been determined. METHODS: We studied 1007 patients with diagnosed Huntington's disease from 565 families and 43 national and ethnic groups. In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2). The number of CAG repeats was also assessed in 1595 control chromosomes, with the size of adjacent polymorphic CCG trinucleotide repeats taken into account. RESULTS: Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent). There were no significant differences among national and ethnic groups in the number of repeats. No CAG expansion was found in the 110 control subjects with other neuropsychiatric disorders (specificity, 100 percent; 95 percent confidence interval, 95.2 to 100 percent). In 1581 of the 1595 control chromosomes (99.1 percent), the number of CAG repeats ranged from 10 to 29 (median, 18). In 12 control chromosomes (0.75 percent), intermediate-sized CAG sequences with 30 to 35 repeats were found, and 2 normal chromosomes unexpectedly had expanded CAG sequences, of 39 and 37 repeats. CONCLUSIONS: CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.
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By 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including Huntington's disease and cystic fibrosis.
“by 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including many with substantial biomedical impact, such as Huntington’s disease and cystic fibrosis7–9.”
From A brief history of human disease genetics (2020) · cites this paper as [7]
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- Authors
- Kremer, B., Goldberg, P., Andrew, S. E., Theilmann, J., Telenius, H., Zeisler, J., Squitieri, F., Lin, B., Bassett, A., Almqvist, E., Bird, T. D., & Hayden, M. R.
- Affiliations
- University of British Columbia (CA)
- University of Cape Town (ZA)
- Karolinska University Hospital (SE)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1994-05-19
- Volume
- 330
- Issue
- 20
- Pages
- 1401-1406
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2317137640
- Cited by
- 602
- References
- 38
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 27 · 2023: 11 · 2022: 21 · 2021: 28 · 2020: 23 · 2019: 23 · 2018: 16 · 2017: 21 · 2016: 20 · 2015: 23 · 2014: 24 · 2013: 24 · 2012: 22
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AGO 5136)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- Huntington's disease, CAG repeat expansion, trinucleotide repeat expansion, sensitivity and specificity, genetic testing, ethnic groups, neuropsychiatric disorders, hereditary chorea, dentatorubropallidoluysian atrophy, neuroacanthocytosis, Alzheimer's disease, schizophrenia, major depressive disorder
- MeSH terms
- Adult, Alleles, Chromosomes, Human, Pair 4, Diagnosis, Differential, DNA, Humans, Huntington Disease, Mutation, Oligodeoxyribonucleotides, Polymorphism, Genetic, Repetitive Sequences, Nucleic Acid, Sensitivity and Specificity
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