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February 3, 1993

Triplet Repeat Mutations: Amplification Within Pedigrees Generates Three Human Diseases

JAMA. 1993;269(5):558-562. doi:10.1001/jama.1993.03500050016004

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AN UNSTABLE DNA sequence, made up of three contiguously repeating nucleotides, has been pinpointed recently as the genetic cause of fragile X syndrome, myotonic dystrophy, and Kennedy disease. This novel mutation provides a specific molecular mechanism behind the phenomenon of anticipation— the clinical observation that some genetic diseases manifest at either an earlier age or more severely in successive generations. (Please refer to accompanying article.)

The consequences of this unstable sequence vary widely, depending on the gene in which it occurs and its location within the gene. So too does the number of repeats that lead to normal, mildly, and severely affected outcomes. The following summarizes more than a dozen presentations on this topic at the recent annual meeting of the American Society of Human Genetics.

Kennedy Disease  In early 1991, researchers identified an expansion of the CAG trinucleotide repeat sequence in the androgen receptor gene of patients with X-linked