NEW YORK – Using genome sequence data, a team from the UK, the US, and Italy has demonstrated that disease alleles linked to repeat expansion disorders (REDs) turn up roughly 10 times more often in human populations than previously believed.
"These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs," senior and corresponding author Arianna Tucci, a researcher at Queen Mary University of London and University College London's Institute of Neurology, and colleagues wrote in a study published in Nature Medicine on Tuesday.
"There are currently no disease-modifying treatments for REDs; however, both disease-specific treatments and drugs that target the mechanisms leading to repeat expansions are in development," the authors added, noting that "[w]e have established that the number of people who may benefit from such treatments is greater than previously thought."
For their study, the researchers analyzed whole-genome sequencing data for 82,176 individuals enrolled in the 100,000 Genomes Project or the Trans-Omics for Precision Medicine (TOPMed) program, using data from phase 3 of the 1,000 Genomes Project to genetically predict participants' ancestry.
"As the data for the cohort in which we carried out this study were collected for medical sequencing purposes, we controlled for factors potentially leading to overestimating disease allele carrier frequency," the authors noted, "such as excluding people with neurological disorders and checking that there was no selection bias for patients with [myotonic dystrophy type 1], which can cause cardiac abnormalities."
The team searched for mutation or premutation alleles of genes known to be involved in REDs, including sequences for 59,568 individuals of European ancestry, 12,786 of African ancestry, 2,882 of South Asian ancestry, 1,266 individuals of East Asian ancestry, and 5,674 American participants.
Though past studies had implicated REDs in neurological and other conditions affecting roughly one in 3,000 individuals globally, the authors noted that "prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and technological limitations leading to under-ascertainment."
In contrast to past RED profiling efforts that relied on PCR assays or Southern blot analyses, the team explained, the new genome sequencing-based analyses suggested that one in every 283 individuals carry RED alleles, on average. Premutation alleles were even more common, turning up in one in every 64 participants.
"The finding that a much larger number of people in the general population carry pathogenic alleles of REDs has important implications both for diagnostic and genetic counseling of RED," the authors reported.
In particular, their modeling efforts suggested REDs may affect two- to threefold more individuals than are recognized in existing disease reports, depending on disease penetrance patterns.
The expansions they uncovered fell in more than a dozen genes such as C9orf72, DMPK, ATXN1, ATXN2, ATXN3, HTT, and FXN, which have been linked to conditions such as amyotrophic lateral sclerosis, myotonic dystrophy, ataxia conditions, and Huntington disease.
While the repeat expansions turned up across genetic ancestry groups, the investigators saw higher or lower rates of certain REDs in specific populations.
They noted that rare Huntington disease-like 2-related expansions in the JPH3 gene were found at higher-than-usual rates in African ancestry individuals, for example, while pathogenic repeat expansions in the RFC1 gene turned up less frequently in this group than in others. On the other hand, participants of East Asian ancestry showed an uptick in ATN1, TBP, and NOTCH2NLC gene expansions, and those with European ancestry carried more frequently expansions affecting FXN, C9orf72, and DMPK.
Likewise, the investigators found variability in the length of the pathogenic repeats, including ancestry-associated variations that may contribute to differences in RED epidemiology.
"Given the relationship between the size of the repeat expansion and the disease onset and progression, it is possible that individuals carrying alleles currently classified as fully penetrant … may sometimes remain asymptomatic," the authors wrote, adding that "[f]urther research is needed to study the potential role of population-specific cis and trans genetic modifiers of repeat expansion mutations that underlie the marked global differences in prevalence found in the present study."