Molecular diagnosis of muscular diseases in outpatient clinics

Abstract

ObjectiveTo evaluate the diagnostic yield of an 89-gene panel in a large cohort of patients with suspected muscle disorders and to compare the diagnostic yield of gene panel and exome sequencing approaches.MethodsWe tested 1,236 patients from outpatient clinics across Canada using a gene panel and performed exome sequencing for 46 other patients with sequential analysis of 89 genes followed by all mendelian genes. Sequencing and analysis were performed in patients with muscle weakness or symptoms suggestive of a muscle disorder and showing at least 1 supporting clinical laboratory.ResultsWe identified a molecular diagnosis in 187 (15.1%) of the 1,236 patients tested with the 89-gene panel. Diagnoses were distributed across 40 different genes, but 6 (DMD, RYR1, CAPN3, PYGM, DYSF, and FKRP) explained about half of all cases. Cardiac anomalies, positive family history, age <60 years, and creatine kinase >1,000 IU/L were all associated with increased diagnostic yield. Exome sequencing identified a diagnosis in 10 (21.7%) of the 46 patients tested. Among these, 3 were attributed to genes not included in the 89-gene panel. Despite differences in median coverage, only 1 of the 187 diagnoses that were identified on gene panel in the 1,236 patients could have been potentially missed if exome sequencing had been performed instead.ConclusionsOur study supports the use of gene panel testing in patients with suspected muscle disorders from outpatient clinics. It also shows that exome sequencing has a low risk of missing diagnoses compared with gene panel, while potentially increasing the diagnostic yield of patients with muscle disorders.

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

“…Punetha et al carried out targeted sequencing with a myopathy candidate gene panel in a cohort of 94 undiagnosed muscle disease patients and obtained the diagnostic yield of 35% [ 18 ]. In recent study, Thuriot et al used gene panel approach in a large cohort of patients with suspected muscle disorders and reported an overall diagnostic yield of 15.1% (22.4% in children and 13.7% in adults) [ 19 ]. Most of other reported NGS based studies focused on one or more types of myopathy, including congenital muscular disorder [ 5 , 8 , 11 , 13 ], LGMD [ 5 , 6 , 8 , 10 , 12 , 14 ], or DM [ 7 , 12 ].…”

“…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].…”

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

“…Whole-exome sequencing (WES) allows rapid, low cost and unbiased identification of pathogenic variants in patients with suspected genetic diseases. [1][2][3][4][5] But, the large amount of information provided by this powerful gene discovery tool can be timeconsuming and often yields inconclusive results. The use of gene lists can improve diagnostic yield by filtering patient WES results to those variants identified in genes associated with disease-causing mutations.…”

Lessons of the month: A breathless severe asthmatic in the genomic era: Occam's razor or Hickam's dictum?

“…Given this clinical presentation, and knowledge that her son had mild hypotonia, she underwent genetic testing of 94 genes associated with muscle disorders. 4 Pathogenic variants were detected in two genes: FLNC (NM_001458.4: c.7371delT; p.Ser2457fs) and CHRNE gene (NM_000080.3: c.448C>T; p.Ser163Leu). A diagnosis of filamin-C-related fibrillary myopathy was determined responsible for her myopathy based on the presence of the FLNC variation, which is known to cause a frameshift and introduce a premature stop codon in exon 44, with resultant nonsense-mediated messenger ribonucleic acid decay and haplo-insufficiency.…”