The Exome Clinic and the Role of Medical Genetics Expertise in Interpretation of Exome Sequencing Results

PURPOSE: Evaluation of the clinician’s role in optimal interpretation of clinical exome sequencing (ES) results. METHODS: Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results. RESULTS: The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). The overall diagnostic yield was 36% based on sequencing data. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield was increased to 43%. Seven patients of our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. The clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases. CONCLUSIONS: Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of post-analytical diagnostic work-up in solving the “diagnostic odyssey.”