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

Abstract

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 (~66%), followed by multiple congenital anomalies (~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." Genet Med advance online publication 02 March 2017.

Figure 1. Cost and phenotypic characterization of the cohort

A) Scatter plot of the out-of-pocket cost in ascending order. B) Each case was assigned a phenotype-based, single primary indication for performing ES. The number and percentage of cases are shown in parenthesis. MCA: Multiple congenital anomalies. C) Each phenotypic feature of the probands was assigned to an organ system, and the total count of cases is displayed. D) The frequency and distribution of the neurodevelopmental phenotypes in the cohort. The darker portion of the bar in C and D indicates the proportion of cases that achieved a definitive diagnosis.

Figure 2. Characterization of case-level and clinical-level assertions

A) The relative percentages of each case-level classification as reported by the testing laboratory. B) The diagnostic rates according to case-level and clinical-level assertions are shown as the proportion of cases, in gray. The change in classification of cases is indicated, with 16 cases promoted and 5 demoted.