Repeat Expansion Mutations More Common Than Thought

Repeat expansion disorders, which are responsible for more than 40 neurological diseases, may be more common than clinical data would suggest. Epidemiological studies had estimated that REDs affect about one in 3,000 people, but now a study led by Arianna Tucci at the Queen Mary University of London predicts that this figure may be two- to threefold higher. In the October 1 Nature Medicine, the scientists report the largest whole-genome sequencing analyses of repeat expansions using data from 82,176 unrelated individuals across different populations. They found that one in 283 of these individuals carries repeat alleles that are considered large enough to cause disease. This unexpectedly high incidence suggests that people either go undiagnosed or that they are somehow protected. One in 64 carries an expansion that is borderline pathogenic, meaning their descendants are at risk for disease.

  • More people have a repeat expansion mutation than are diagnosed clinically.
  • Borderline pathogenic expansions are common, threatening future generations.
  • Most expansions are found in all populations.

REDs occur when repeats of two or more nucleotides replicate repeatedly, resulting in pathogenic expansions of DNA that can range from 30 to several thousand base pairs long. For example, Huntington’s disease (HD), the first expansion disorder discovered, occurs when a cysteine-arginine-guanine (CAG) trinucleotide in the HTT gene swells to 40 or more repeats. Such mutations typically begin with a small innocuous expansion that grows gradually and randomly through generations until it becomes pathogenic (see Depienne and Mandel, 2021, for review). This means that even people with no family history could fall victim to one of these diseases if one of their ancestors carries a repeat in the “permutation” range, i.e., not pathogenic, but long enough that any further expansion would be. Thresholds for repeat length pathogenicity, as in HD, have been determined empirically for most REDs.

“It was very important for us to define the number of people in the general population with a pathogenic allele who might go on to develop the disease,” Tucci told Alzforum.

Estimating the number of people with repeat-expansion mutations has been challenging. The repeats are not amenable to typical analytical tools, such as DNA amplification, and precise sizes of the repeats have been hard to pin down by Southern blot. Moreover, repeat expansion within the same locus can lead to different phenotypes. Mutations in the C9ORF72 gene, for example, cause multiple conditions, including amyotrophic lateral sclerosis, frontotemporal dementia, and even Huntington-like disease (Gossye et al., 2020). 

Tucci and her colleagues tackled two main questions: How prevalent are repeat expansion mutations, and does that vary across different populations? They analyzed whole-genome sequencing (WGS) data from two large cohorts: the 100,000 Genomes Project from the National Health Service in the U.K. and Trans-Omics for Precision Medicine from the National Institutes of Health (NIH) in the U.S. Because the technique is only accurate for a read length of less than 150 base pairs, the researchers were limited to analyzing a fraction of the more than 40 known REDs (Ibañez et al., 2022). Some genes, such as FMR1, a cause of fragile X syndrome, can have expansions of more than 200 repeats. Still, the researchers were able to analyze the prevalence of 16 RED loci in individuals of European, African, American, South Asian, and East Asian descent. These mutations cause a wide range of neurological diseases including spinocerebellar ataxia, Friedreich ataxia, myotonic dystrophy, Huntington’s disease, and C9ORF72-related diseases

Population Differences. Among 16 REDs (colored bars), the proportion of each varies by genetic ancestry. Africans have the most diverse range of mutations, occurring in all REDs except for CACNA1A, a gene that causes a range of neurological disorders including ataxia and epilepsy. The East Asian population had the most striking distribution of genes, with the largest number of people carrying the TBP gene expansion that causes SCA17, and no FXN and DPMK expansions. (AFR, African; AMR, American; EAS, East Asian; EUR, European; SAS, South Asian.) [Courtesy of Ibañez et al., 2024.]

“The major strengths of this study include the large sample size across different ethnicities, even though it was still predominantly Eurocentric, and the analysis of a large number of different RED-associated loci, enabled by applying relatively new bioinformatic tools to WGS datasets,” said Ahmad Aziz, German Centre for Neurodegenerative Diseases in Göttingen.

Based on the number of people who carry expansions long enough to be pathogenic, first author Kristina Ibañez and colleagues estimated that 2.3 per 100,000 people would have Huntington’s disease—three times higher than the reported cases. They saw a similar discrepancy between their estimates and the epidemiological data for six of the most common RED loci—C9ORF72, DM1, HD, SCA1, SCA2, and SCA6—with the biggest difference being for Spinocerebellar ataxia type 6, which they estimated to be ninefold more prevalent than estimated by reports.

Ibañez also found that the number and type of repeat-expansion mutations vary by geographical location, which may explain variation in how the diseases emerge globally. For example, pathogenic alleles in FXN that cause Friederich ataxia are more prevalent in Europeans, whereas those in ATN1 that cause dentatorubral-pallidoluysian atrophy are more common in East Asians, consistent with the disease epidemiology.

Still, most pathogenic RED alleles, such as HTT that causes Huntington’s disease, TATA binding protein (TBP) that causes a rare neurodegenerative disease called spinocerebellar ataxia type 17, and RCF1 that causes late-onset ataxia, were found in all populations. GGGCC expansions in C9ORF72, which were previously thought to occur only in Europeans, also turned up in African and South Asian populations. The data challenge the notion that expansions are population-specific. “That was one of the most unexpected results,” Tucci said. If this expansion occurred independently, it may point to a specific part of the genome that predisposes the genetic expansion globally, she said. Aziz thought this was important as well. “This finding indicates that de novo repeat expansions can arise regardless of ethnic background,” he said.

Another finding that caught the scientists by surprise was the unusually high prevalence of pathogenic TBP repeat expansion across populations. In their dataset, one in 247 individuals had an allele longer than the pathogenic threshold of 40 repeats, yet the prevalence of spinocerebellar ataxia 17, the disease caused by mutations in TBP, was less than one in 100,000. “I think we are getting the threshold wrong,” Tucci said.

Tucci and her colleagues were not the first to investigate the prevalence of REDs. In 2019, Aziz and Sarah Gardiner at Leiden University Medical Center in the Netherlands reported a large study on polyglutamine diseases caused by expanded CAG repeats. They analyzed DNA from 14,196 individuals across five large European population-based cohorts and found that the number of pathogenic polyglutamine mutation carriers were in some cases several hundred times higher than estimated clinically, suggesting that these diseases may be more prevalent than thought. Their estimates were even higher than Tucci and her colleagues’ (Gardiner et al., 2019). For example, they found one in 95 people carried a TBP mutation. Aziz thinks his and Gardiner’s use of less stringent pathogenic thresholds might explain the differences.

Does finding more pathogenic allele carriers than people with disease point to a lack of diagnosis or to a mechanism that protects some carriers from developing the disease? “This is something we need to find out and understand because it will improve our genetic counselling and the way we think about drug treatments,” Tucci said.—Kristel Tjandra

Kristel Tjandra is a freelance writer in Springfield, Virginia.

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References

Paper Citations

  1. Depienne C, Mandel JL. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?. Am J Hum Genet. 2021 May 6;108(5):764-785. Epub 2021 Apr 2 PubMed.
  2. Gossye H, Engelborghs S, Van Broeckhoven C, van der Zee J. C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis. Gene Reviews Gene Reviews
  3. Ibañez K, Polke J, Hagelstrom RT, Dolzhenko E, Pasko D, Thomas ER, Daugherty LC, Kasperaviciute D, Smith KR, WGS for Neurological Diseases Group, Deans ZC, Hill S, Fowler T, Scott RH, Hardy J, Chinnery PF, Houlden H, Rendon A, Caulfield MJ, Eberle MA, Taft RJ, Tucci A, Genomics England Research Consortium. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022 Mar;21(3):234-245. PubMed.
  4. Gardiner SL, Boogaard MW, Trompet S, de Mutsert R, Rosendaal FR, Gussekloo J, Jukema JW, Roos RA, Aziz NA. Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease-Associated Alleles Among Large Population-Based Cohorts. JAMA Neurol. 2019 Jun 1;76(6):650-656. PubMed.

Further Reading

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Primary Papers

  1. Ibañez K, Jadhav B, Zanovello M, Gagliardi D, Clarkson C, Facchini S, Garg P, Martin-Trujillo A, Gies SJ, Galassi Deforie V, Dalmia A, Hensman Moss DJ, Vandrovcova J, Rocca C, Moutsianas L, Marini-Bettolo C, Walker H, Turner C, Shoai M, Long JD, Fratta P, Langbehn DR, Tabrizi SJ, Caulfield MJ, Cortese A, Escott-Price V, Hardy J, Houlden H, Sharp AJ, Tucci A. Increased frequency of repeat expansion mutations across different populations. Nat Med. 2024 Oct 1; PubMed.

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