Clinical Edge

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Polyglutamine Diseases Are Rare, But Not Mutations That Cause Them

Key clinical point: Vastly more people carry mutations implicated in Huntington disease and other neurodegenerative diseases than previously estimated.

Major finding: Among the study subjects, 10.7% had CAG repeats sufficient to put offspring at risk of disease, while 1.3% had enough repeats to cause disease.

Study details: A cross-sectional study using genetic information from 14,000 Europeans without a diagnosis of polyglutamine disease.

Disclosures: The Dutch government and European Union sponsored the study. One coauthor disclosed industry support.


Gardiner et al. JAMA Neurol. 2019 Apr 1. doi: 10.001/jamaneurol.2019.0423.


Gardiner et al. describe the results of an appraisal of polyglutamine expansion variants in more than 14,000 individuals from the Netherlands, Scotland, and Ireland. Given the relative rarity of polyglutamine repeat disease, the first question that comes to mind is why were so many individuals identified with repeats in the pathogenic range? Based on our understanding of disease prevalence, it is unlikely that each of these individuals will become affected; therefore, this work suggests a reduced penetrance of these mutations. The findings are illustrative of a growing theme in human disease genetics: There are a very large number of apparently healthy individuals in the general population who carry mutations associated with various diseases. The phenomenon of reduced penetrance, where mutations cause disease in some but not all carriers, overlaps and arguably may be the same as that of variable expressivity, where the same mutation can lead to very different disease outcomes in different individuals. It is extremely likely that second-generation sequencing and population-scale screening will continue to reveal similar themes. We continue to appreciate the increasing complexity of the human genome and its relationship to disease, even those diseases we thought of previously as simple “single-gene” disorders.

Monia B. Hammer, PhD, and Andrew B. Singleton, PhD, are with the National Institute on Aging, National Institutes of Health, Bethesda, Md. Dr. Hammer and Dr. Singleton report no financial conflicts of interest related to their editorial.