Abstract
Abstract
Myotonic Dystrophy type 1 (DM1) is a multisystem disorder caused by CTG repeat expansions in the dystrophia myotonica protein kinase (DMPK) gene. Current prevalence estimates of 1 in 3,000-8,000 have traditionally relied on clinically ascertained and geographically restricted cohorts, underestimating population burden and failing to capture ancestry diversity. Using large-scale whole-genome sequencing (WGS) datasets, we aimed to identify DMPK repeat expansions across nearly one million participants, define their ancestry-specific distribution, and evaluate associated clinical phenotypes, with particular focus on cardiac manifestations and early-onset cataracts.
We analysed WGS participants from three cohorts: Genomics England (n = 80,110), UK Biobank (n = 490,086), and the All of Us Research Program (n = 414,830). DMPK repeat lengths were estimated using ExpansionHunter. Alleles were classified as Normal (≤37 repeats), Intermediate (38-49 repeats), or Pathogenic (≥50 repeats). Genetic ancestry was assigned using cohort-specific methods. Linked health record data assessed cardiac phenotypes in UK Biobank and early-onset cataracts in Genomics England and UK Biobank.
Across all cohorts (n = 985,026), pathogenic DMPK repeat expansions were identified in 645 individuals (0.07%; ∼1 in 1,527), a prevalence two-to-five times higher than previous estimates. Most expansions occurred in those of European ancestry, although expansions were detected across all groups, including up to 1 in 6,693 African and Asian ancestry. In UK Biobank, individuals with a pathogenic expansion had increased odds of any cardiac diagnosis (odds ratio [OR]: 2.06, 95% confidence interval [CI]: 1.58–2.67; p = 5.8×108) and greater cardiac diagnostic burden (risk ratio 2.46, CI: 1.92–3.15; p = 1.6×10−13). Conduction abnormalities—particularly atrioventricular and left bundle-branch block, atrial fibrillation, and flutter—showed the strongest association with expansion status (OR: 4.86, CI: 3.38–6.79; p = 2.7×10−18). No sex differences were observed among those with a DMPK expansion, although male sex was independently associated with conduction disease in the overall population. Approximately one-in-ten individuals with pathogenic expansions had a cataract diagnosis before age 55. Most individuals with an expansion had no prior DM1 diagnosis, highlighting the value of systematic genetic testing in these phenotypes to improve diagnosis, shorten the diagnostic interval, and mitigate harm.
By integrating WGS data from nearly one million individuals, this study refines understanding of the population distribution and clinical consequences of DMPK repeat expansions, revealing a reservoir of undiagnosed and potentially untreated multisystemic disease. These findings support routine inclusion of DMPK analysis within specified cardiac and ophthalmic diagnostic pathways to enable earlier detection.