Genetic 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. 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.

Diagnostic yield of exome sequencing in myopathies: Experience of a Slovenian tertiary centre

“…Using targeted gene panel NGS diagnostic approach they obtained the diagnostic yield of 36%. Bugiardini et al applied focused exome sequencing to investigate complex adult myopathy patients, which were categorized based on the age of symptom onset and predominant pattern of weakness [ 16 ]. Pathogenic or likely pathogenic variants were identified in 32% of cases.…”

“…A growing body of literature has been investigating the benefits and the challenges of NGS based technology implementation in the standard clinical practice of patients with inherited myopathies [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. So far, however, fewer studies have been conducted on patients with unselected primary muscular disease, whereas reported diagnostic yield ranged between 16% and 36% [15][16][17][18][19]. Park et al included only patients, who presented with a specific clinical myopathy pattern [14].…”

“…In recent years, there has been an increasing amount of studies conducted on subgroups of patients with a specific myopathy pattern, including patients with congenital muscular disorders, limb girdle muscular dystrophies or distal myopathies [4][5][6][7][8][9][10][11][12][13][14]. However, far less attention has been paid to the accuracy and efficiency of sequencing technology in unselected group of patients with various myopathy diagnoses [15][16][17][18][19].…”

“…There is a high variability in selection of NGS based diagnostic approaches for characterisation of patients with myopathies and the diagnostic yield obtained from the implementation of such methodologies varies significantly between studies [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Targeted gene panel sequencing approach was commonly used, but the selection of targeted genes differs greatly both in number and composition of genes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

247th ENMC International Workshop: Muscle magnetic resonance imaging - Implementing muscle MRI as a diagnostic tool for rare genetic myopathy cohorts. Hoofddorp, The Netherlands, September 2019

“…Jasper Morrow expanded on the correlation between MRI and clinical data. As muscle MRI provides much greater anatomical specificity than clinical assessments, therefore a perfect correlation between MRI and clinical data is not expected, or indeed desirable [63] . However, demonstrating correlation is vital to provide criterion validity to quantitative muscle MRI as a surrogate outcome measure in NMD.…”