Around one in three people with distal myopathy in Northern Ireland have no genetic diagnosis, and many are mistakenly treated for a different nerve condition instead. This matters because the wrong diagnosis means patients miss out on monitoring for serious heart and breathing problems that often accompany these muscle diseases. The research team has already found a founder mutation in the GNE gene unique to the Northern Irish population, and noticed that deep finger flexor weakness—once thought to be linked to a specific variant—appears across different GNE mutations. Now they will recruit patients with and without known genetic causes, using detailed clinical exams, muscle ultrasound of hands and feet, and long-read whole genome sequencing to find hidden structural variants that standard tests miss. If successful, this work could give doctors clear diagnostic clues to distinguish distal myopathies from similar conditions, improve monitoring for cardiac and respiratory complications, and expand the genetic understanding of these rare diseases in a population with a small gene pool.
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This cross-sectional study aims to establish comprehensive phenotype-genotype correlations in patients with distal myopathies across Northern Ireland. A significant proportion of patients with clinical features of distal myopathy remain without genetic diagnosis, as traditional short-read sequencing may miss structural variants and complex regions relevant to disease. In addition, these rare conditions are frequently misdiagnosed as hereditary motor neuropathies, potentially leading to inadequate monitoring of the known cardiac and respiratory complications which are common in many distal myopathy subtypes. Previous work has yielded two significant findings making this research project important: the identification of a distal myopathy (GNE) founder mutation in the Northern Irish population and the observation of a characteristic pattern of deep finger flexor weakness in our GNE myopathy patients. This pattern, initially thought to be variant-specific, appears to be a consistent feature across different GNE variants. Given Northern Ireland's small gene pool and the presence of specific variants for other neuromuscular conditions, we hypothesise similar population-specific variants may exist in this cohort. In addition, specific diagnostic clues may be revealed through deep phenotyping of this cohort. The study will recruit cases with confirmed mutations in known distal myopathy genes, along with genetically undiagnosed cases. We will employ detailed clinical assessment, muscle ultrasound of hands and feet, and long-read whole genome sequencing (LRWGS) for undiagnosed cases. This research will provide valuable insights into distinguishing features of distal myopathies while expanding genetic understanding of these conditions in the Northern Irish population.
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