To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.
We prospectively enrolled 297 probands who met eligibility ...criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.
Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses.
We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.
Cases of acquired rippling muscle disease in association with myasthenia gravis have been reported. We present three patients with iRMD (immune-mediated rippling muscle disease) and AChR-antibody ...positive myasthenia gravis.
None of them had thymus pathology. They presented exercise-induced muscle rippling combined with generalized myasthenia gravis. One of them had muscle biopsy showing a myopathic pattern and a patchy immunostaining with caveolin antibodies. They were successfully treated steroids and azathioprine. The immune nature of this association is supported by the response to immunotherapies and the positivity of AChR-antibodies.
Schematic representation of Caveolin-3 (CAV3) and its relationship with other muscle proteins. Display omitted
•Rippling muscle is a self-propagating stiffness induced by percussion.•Immunogenic rippling muscle associated to myasthenia gravis was described.•This uncommon association might be underrecognized between myasthenic patients.•The good response to immunotherapy supports their immunologic origin.
Abstract Cases of acquired rippling muscle disease in association with myasthenia gravis have been reported. We present three patients with iRMD (immune-mediated rippling muscle disease) and ...AChR-antibody positive myasthenia gravis. None of them had thymus pathology. They presented exercise-induced muscle rippling combined with generalized myasthenia gravis. One of them had muscle biopsy showing a myopathic pattern and
a patchy immunostaining with caveolin antibodies.
They were successfully treated steroids and azathioprine. The immune nature of this association is supported by the response to immunotherapies and the positivity of AChR-antibodies.
The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in ...clinical genetic diagnostics, including the application of whole‐exome sequencing and next‐generation sequencing‐based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq‐based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations.
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