Literature Review

Polyglutamine diseases are rare, but not the mutations that cause them

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Unpacking disease-causing variants in healthy people

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.



Polyglutamine diseases are a group of hereditary neurodegenerative disorders caused by mutations in which a trinucleotide repeat expands pathologically on a disease-associated gene. The diseases are rare, with the most common among them – Huntington disease – affecting between 10 and 14 per 100,000 people in Western countries, where prevalence is highest.

In polyglutamine diseases, which include the spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy, higher CAG (cytosine-adenine-guanine) repeat numbers are associated with greater disease severity, faster progression, or earlier age at onset.

In research published April 1 in JAMA Neurology, investigators report that more than one-tenth of the European population carries CAG expansions that fall short of the repeats needed to cause any of 9 polyglutamine diseases – but are enough to put them at risk of having children who develop one. A smaller number of people – about 1% – carry enough CAG repeats to cause one of the diseases late in life.

For their research, Sarah L. Gardiner, MD, of Leiden (the Netherlands) University, and her colleagues looked at polyglutamine expansion variants for nine diseases in samples from 14,196 adults (56% of whom were women) from the Netherlands, Scotland, and Ireland. The samples were taken from five population-based cohort studies conducted between 1997 and 2012, and all subjects were without a history of polyglutamine disease or major depression.

Of these, 10.7% had a CAG repeat number on a disease-associated gene that was in the intermediate range, defined as a number of repeats that cannot cause disease but for which “expansion into the fully pathological range has been observed on intergenerational transmission,” Dr. Gardiner and her colleagues wrote. And some 1.3% of subjects were found to have CAG repeats within the disease-causing range, “mostly in the lower range associated with elderly onset.”

The investigators found no differences in sex, age, or body mass index between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range.

Whether carriers of immediate or lower-range pathological CAG repeats went on to develop disease could not be measured, as follow-up data were not available. Another limitation of the study, the investigators acknowledged, was that the genotyping method used “did not allow us to determine the presence of trinucleotide interruptions,” which can affect disease penetrance.

“A late age at onset, a reduced penetrance, or the presence of interruptions could all explain the asymptomatic status of our carriers of intermediate and pathological polyglutamine disease–associated alleles at the time of assessment,” Dr. Gardiner and her colleagues wrote.

This study was funded by the European Union and Dutch government agencies; one of the population-based cohort studies from which the study sample was taken received some support from Bristol-Myers-Squibb. One of Dr. Gardiner’s coauthors, Raymund A. C. Roos, MD, PhD, disclosed being an adviser for UniQure, a gene-therapy firm, and no other conflicts of interest were reported.

SOURCE: Gardiner et al. JAMA Neurol. 2019 Apr 1. doi: 10.001/jamaneurol.2019.042.

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