Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre
| Autor: | Alexander M. Rossor, Matt Parton, David S. Lynch, Michael G. Hanna, Enrico Bugiardini, Qiang Gang, Andrea Cortese, Jasper M. Morrow, Lucy Feng, Ros Quinlivan, Janice L. Holton, Aisling Carr, Alaa Khan, Alan Pittman, Mary M. Reilly, Rahul Phadke, Chris Turner, Julian Blake, Henry Houlden, Emma Matthews |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Muscle Proteins Bioinformatics 03 medical and health sciences 0302 clinical medicine Gene panel Humans Medicine Medical diagnosis Myopathy Pathological Genetics (clinical) Exome sequencing Aged Aged 80 and over Genetic heterogeneity business.industry High-Throughput Nucleotide Sequencing Middle Aged Phenotype 030104 developmental biology Neurology Mutation Pediatrics Perinatology and Child Health Cohort Female Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery Myopathies Structural Congenital |
| Zdroj: | Neuromuscular Disorders. 29:747-757 |
| ISSN: | 0960-8966 |
| Popis: | Diagnosis of inherited myopathies can be a challenging and lengthy process due to broad genetic and phenotypic heterogeneity. In this study we applied focused exome sequencing to investigate a cohort of 100 complex adult myopathy cases who remained undiagnosed despite extensive investigation. We evaluated the frequency of genetic diagnoses, clinical and pathological factors most likely to be associated with a positive diagnosis, clinical pitfalls and new phenotypic insights that could help to guide future clinical practice. We identified pathogenic/likely pathogenic variants in 32/100 cases. TTN-related myopathy was the most common diagnosis (4/32 cases) but the majority of positive diagnoses related to a single gene each. Childhood onset of symptoms was more likely to be associated with a positive diagnosis. Atypical and new clinico-pathological phenotypes with diagnostic pitfalls were identified. These include the new emerging group of neuromyopathy genes (HSPB1, BICD2) and atypical biopsy findings: COL6A-related myopathy with mitochondrial features, DOK7 presenting as myopathy with minicores and DES-related myopathy without myofibrillar pathology. Our data demonstrates the diagnostic efficacy of broad NGS screening when combined with detailed clinico-pathological phenotyping in a complex neuromuscular cohort. Atypical clinico-pathological features may delay the diagnostic process if smaller targeted gene panels are used. |
| Databáze: | OpenAIRE |
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