EP.103Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre

Abstract

Diagnosis of inherited myopathies can be a challenging and lengthy process due to broad genetic and phenotypic heterogeneity. The advent of next generation sequencing (NGS) has revolutionised diagnostic capabilities by allowing for rapid parallel screening of multiple genes. In our study we screened with focused exome sequencing 100 adult patients with a clinical diagnosis of inherited myopathy but no genetic confirmation despite extensive investigations. We assessed the frequency and variability of genetic diagnoses and clinical factors most likely to be associated with a positive diagnosis. We also detailed clinical pitfalls and new phenotypic insights that will aid in future diagnosis. We identified pathogenic/likely pathogenic variants in 32/100 patients, in most cases related to a single gene each. TTN-related myopathy was diagnosed in 4/32 cases. Features more likely to be associated with a genetic diagnosis included younger age of onset, abnormal MRI and/or EMG. Atypical phenotypes with diagnostic pitfalls were identified. These include the group of neuro-myopathy genes (HSPB1, BICD2), COL6A-related myopathy with mitochondrial abnormality, DOK7 presenting as myopathy with minicores and DES-related myopathy without myofibrillar pathology. In one case a FLNA-related disease mimicking a congenital myopathy was identified. Diagnosis is often challenging due to the heterogeneity of clinical manifestations, atypical phenotypes and lack of diagnostic markers that are specific to a single genetic diagnosis. Our study demonstrates the diagnostic efficacy of broad NGS screening in complex neuromuscular cohort when combined with a multi-disciplinary assessment.