Huntington disease without CAG expansion: Phenocopies or errors in assignment?

Susan E. Andrew, Y. Paul Goldberg, Berry Kremer, Ferdinando Squitieri, Jane Theilmann, Jutta Zeisler, Håkan Telenius, Shelin Adam, Elisabeth Almquist, Maria Anvret, Gerard Lucotte, A. Jon Stoessl, Giuseppe Campanella, Michael R. Hayden

Research output: Contribution to journalArticlepeer-review


Huntington disease (HD) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16.3 (IT15). A total of 30 of 1,022 affected persons (2.9% of our cohort) did not have an expanded CAG in the disease range. The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD. Here we show that the majority (18) of the individuals with normal sized alleles represent misdiagnosis, sample mix-up, or clerical error. The remaining 12 patients represent possible phenocopies for HD. In at least four cases, family studies of these phenocopies excluded 4p16.3 as the region responsible for the phenotype. Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases; however, in as many as seven of these persons, retrospective review of these patients' clinical features identified characteristics not typical for HD. This study shows that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD.

Original languageEnglish
Pages (from-to)852-863
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Genetics


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