Amended Informative Negative Whole Exome Sequencing Results

Abstract Background: Whole exome sequencing (WES) is widely used as a first-tier diagnostic test. The diagnostic yield for WES is estimated at approximately 50%, leaving the requesting clinician with 50% ambiguous or negative results in cases where the diseases-causing variants could not be identified. Methods: We retrospectively assessed the results of all WES tests requested from 2015 to 2018 at our institution. We included participants with a negative test result, irrespective of the phenotype. Complete data collection, medical-record extraction, and additional analysis were done for qualifying cases. Results: The cohort included 151 participants with a negative WES result. Of the sample, 18% (n=27) were discharged from the genetic clinic, and only three cases required additional genetic testing prior to discharge. The decision to discharge a patient was based on several factors, including a mild phenotype (i.e. a phenotype that can be resolved and doesn’t require surgical, rehabilitation or medical intervention), a confirmed multifactorial condition, or the patient is developing according to the milestones for his age group and has a negative family history. The discharge rate and the period of being followed at the clinic improved over time. In 2015, none was discharged, and in 2016, nearly 100% of the negative cases were discharged in 6-12 months. In 2017, 65% of the cases were discharged in less than six months, and all cases tested in 2018, were discharged from the clinic in less than three months.Conclusion: Informative negative WES results lower the cost of additional testing, reduce the number of follow-up consultations, and result in the reassurance or discharge the patient. The informative negative WES results (18%) can be combined with the hit rate of the WES (50%) in consanguineous population, increasing the clinical utility of WES testing to 68%.