CM Reuter1,8, JN Kohler1, D Bonner1, DB Zastrow1, M Majcherska1, L Fernandez1, C McCormack1, S Marwaha1, C Curnin1, J Hom1,2, J Sampson1,3, M Ruzhnikov1,3,4, S Sutton1,5, AM Dries1, C Zhao1,7, Y Huang1,7, E Brimble1,3, Undiagnosed Diseases Network6, PG Fisher1,5,6, JA Bernstein1,4,5, EA Ashley1,7,8, MT Wheeler1,7,8.
1Stanford Center for Undiagnosed Diseases, Stanford Medicine; 2Department of Medicine, Stanford Medicine; 3Department of Neurology, Stanford Medicine; 4Department Pediatrics – Medical Genetics, Stanford Medicine; 5Department of Genetics, Stanford Medicine; 6NIH Undiagnosed Diseases Network, Office of the Director and the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. 7Division of Cardiovascular Medicine, Stanford Medicine; 8Center for Inherited Cardiovascular Diseases, Stanford Medicine
Introduction: The Stanford Center for Undiagnosed Diseases (CUD) is a clinical site of the Undiagnosed Diseases Network (UDN). The CUD enrolls patients with rare, undiagnosed diseases across various clinical indications including those with undiagnosed cardiovascular disease. The mission of the UDN is to improve knowledge of the molecular etiology of disease and to develop bioinformatic tools to support precision medicine. Since 2015, the CUD has enrolled 153 of 359 patients who applied (42.6%). The primary phenotype is cardiovascular in twelve patients (7.8%). To date, evaluation in the CUD has yielded a confirmed diagnosis in two of twelve patients with cardiovascular phenotypes and 29 of 106 patients overall.
Case Report: A 32-year-old female presented with a 10-year history of persistent intermittent chest pain and troponin elevation (>20 mg/dL) of unclear etiology, borderline left ventricular (LV) ejection fraction (55%), hypokinesis of the LV wall, mesocardial myocardial fibrosis, mild endothelial dysfunction, and sinus tachycardia. Repeated coronary catheterizations showed no epicardial coronary artery disease and PET CT showed no evidence of myocardial inflammation. Her extensive clinical workup had failed to identify a unifying diagnosis. Prior clinical exome sequencing was recommended, but coverage was denied by the patient’s insurance provider. The patient was thus referred to the CUD. Evaluation in the CUD included clinical exome sequencing. A heterozygous pathogenic nonsense variant was identified in the DSP gene (c.1273C>T; p.Arg425Ter). Pathogenic variants in DSP are associated with both dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. While the patient’s cardiac imaging did not reveal any LV enlargement or right ventricular involvement, case reports of patients with DSP nonsense variants have described similar presentations with elevated troponin, chest pain, and fibrosis in the absence of ventricular enlargement. Thus, we considered the DSP variant to be diagnostic. The patient has since established care with a heart failure cardiologist and electrophysiologist for ongoing surveillance and sudden death risk stratification.
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