Mining clinical and genomic data is a powerful tool whose full diagnostic potential is bearing fruit in exciting new ways. For instance, investigators at the University of British Columbia (UBC)/Centre for Molecular Medicine & Therapeutics (CMMT) and BC Children’s Hospital decided to comb through 25 years of data searching for new insights into predicting the age of onset for Huntington’s disease. Huntington’s disease is an inherited disorder that affects one in approximately 10,000 humans and for every affected person, there are four to five individuals that carry the gene mutation that causes the disease but are not yet ill—underscoring the need for better predictive biomarkers.
Findings from this new study were published recently in the American Journal of Human Genetics through an article titled “Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington’s Disease.”
“This discovery may enable us to provide families with additional information,” said lead study investigator Galen Wright, PhD, a research associate in the UBC faculty of medicine. “It could also potentially improve disease management by providing genetic counselors with valuable data in the future.”
Huntington’s disease is caused by a single mutation in the huntingtin gene, where patients carry an expanded stretch of repetitive DNA. While the length of this mutation has long been regarded as the greatest indicator of when (and whether) an individual will exhibit symptoms of the disease, researchers at UBC have uncovered a genetic variant that also significantly influences age of onset in patients.
“Our study reveals that age of onset in Huntington’s disease is influenced not only by the length of the expansion mutation but also by the DNA sequence directly adjacent to this repetitive sequence,” said senior study investigator Michael Hayden, PhD, a professor of medical genetics and director emeritus for the CMMT, which is part of the faculty of medicine at UBC and located at BC Children’s.
This is the key finding in a new study published today in the American Journal of Human Genetics. While previous studies of the huntingtin gene have focused on the length of the string of glutamine building blocks in the DNA of the gene, this study examined variants in the DNA sequence encoding for these glutamine building blocks and the relationship between these variants and the age of onset of the disease.
The DNA sequence that causes Huntington’s disease is primarily made up of repeats of three letters of DNA, CAG, which encode the protein building block, glutamine. But UBC researchers have shown that the presence of another glutamine building block, CAA, significantly impacts the disease. In individuals where the CAA sequence is replaced with a CAG sequence, patients were found to present with the disorder decades earlier than expected, despite carrying an identical number of glutamine amino acids. Moreover, the length of uninterrupted CAG sequence also appears to contribute to somatic instability.
“Now we know that the age of onset in Huntington’s disease is significantly impacted by the length of uninterrupted CAG sequence,” Hayden stated.
The researchers screened samples from patients in the UBC Huntington’s disease biobank for the variant in the huntingtin gene, to examine the age of onset and whether the mutation was more likely to expand to longer repeat lengths in the blood. Hayden established this bank—which now contains approximately 8,000 specimens—in 1986 in an effort to conduct such studies.
Hayden’s team hopes to screen additional DNA samples to further refine the age of onset prediction models for people from families with Huntington disease’s with this variant, and to look at how these variants express themselves in brain tissue.