Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

Abstract

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

“…We did not implement strict inclusion criteria. The success rate from our “catch‐all” cohort is in keeping with similar studies, likely reflecting the experience of other diagnostic centers …”

“…The success rate from our "catch-all" cohort is in keeping with similar studies 10,18 , likely reflecting the experience of other diagnostic centers. 15 Diagnostic success was negatively correlated with PAR. Other cohorts have displayed enrichment of diagnoses in patients <18 years.…”

“…Other cohorts have displayed enrichment of diagnoses in patients <18 years . The higher diagnostic success in patients <18 years, especially infants in intensive care, suggests that later‐onset diseases may be more likely to have a polygenic and/or nongenetic etiology (e.g., diabetes causing a peripheral neuropathy) …”

“…Disease features and laboratory findings are often nonspecific in neuromuscular diseases, particularly early or late in disease progression. 15,16 A comprehensive gene panel is especially useful for heterogeneous diseases as it facilitates diagnosis despite uncertain disease etiology or atypical presentation, and can partly compensate for variable levels of clinical acumen/assessment and/or limited clinical information. 10,[17][18][19] However, detailed clinical information should guide genetic diagnosis and reduce turnaround time.…”

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

“…The 27% diagnostic yield included the 256 patients with one pathogenic and one VUS in the same LGMD gene since it is most likely these VUSs are likely pathogenic as the patients show clinical symptoms and no other variant was identified in the same or any other gene. The diagnostic yield of our study is slightly higher than some previous exome sequencing studies in neurological disorders, even with a substantial patient cohort recruited based on specific disease phenotypes 41, 42. This suggests the importance of using screening criteria of disease‐specific clinical information carefully to judge the type of NGS‐diagnostic testing for patient recruitment (fig.…”