The first 500 diagnostic exomes: A demonstration of safety, clinical utility, translation and cost-effectiveness.

Abstract

Purpose: Whole exome sequencing (WES) is rapidly becoming the standard of care for genetic services. We present the results of 500 clinical exomes performed at the Randwick Genetic Laboratory. Method(s): WES was performed in 204 probands with suspected Mendelian disorders, together with family members. Ampliseq RDY exome, libraries were analyzed on a Life Technologies Proton instrument. Data were analyzed using an in house pipeline with variant reporting following ACMG guidelines. Result(s): WES resulted in greater than 43% definitive findings with a small number of variants of uncertain significance. The diagnostic rate has increased over time, likely reflecting refinements in clinician referral practice as well as improved functionality of bioinformatics pipelines. Two families (1%)with Cantu and MoyaMoya syndromes had results which could lead to pharmacologic interventions. 33 families (16%) had De novo variants and seven (3.5%) were X-linked with significant implications for recurrence risk. Two prenatal diagnoses have been performed based on WES results. A diagnosis was made in 6/8 (75%) rapid turnaround studies, including two during pregnancy. Almost 10% of the diagnoses were unanticipated by the clinical teams and involved significant changes in diagnostic category. Four likely novel genes involved in known biological pathways were identified, enabling research participation. Conclusion(s): The minimum number of management changing outcomes was at least 20% within the 12 month period of this study. The number of secondary findings was small at about 1%. This demonstrates that WES is characterized by high levels of patient safety and clinical utility with likely cost effectiveness.