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Volume 330:1401-1406 May 19, 1994 Number 20 Next

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ABSTRACT

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 113 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.

Source Information

From the Department of Medical Genetics, University of British Columbia, Vancouver (B.K., P.G., S.E.A., J.T., H.T., J.Z., F.S., B.L., M.R.H.); the Clarke Institute of Psychiatry, University of Toronto, Toronto (A.B.); the Karolinska Hospital, Stockholm, Sweden (E.A.); and the Veterans Affairs Medical Center and the Department of Medicine, University of Washington, Seattle (T.D.B.). The following institutions and researchers participated in the study: J. Greenberg, University of Cape Town, Cape Town, South Africa; G. Lucotte, Centre Hospitalier Universitaire-Centre Hospitalier Regional de Reims, Reims, France; M. Anvret, Karolinska Hospital, Stockholm, Sweden; J. Kennedy and A. Petronis, Clarke Institute of Psychiatry, University of Toronto, Toronto; S. Bohlega, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; G. Campanella, Department of Neurology, University of Naples, Naples, Italy; H. Shinotoh and D.B. Calne, Neurodegenerative Disorders Centre, University of British Columbia, Vancouver; S. Adam and C. Benjamin, Department of Medical Genetics, University of British Columbia, Vancouver; W.G. Honer, Department of Psychiatry, University of British Columbia, Vancouver; E. Ives, Memorial University, St. John's, Newfoundland; and G.D. Schellenberg, Department of Medicine, University of Washington, Seattle.

Address reprint requests to Dr. Hayden at the Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Bldg., Vancouver, BC V6T 1Z4, Canada.

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