The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results

Purpose: Evaluation of the clinician's role in the 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 (similar to 66%), followed by multiple congenital anomalies (similar to 10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in 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. 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 postanalytical diagnostic work-up in solving the diagnostic odyssey.