Abstract
There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES. We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups. To determine the clinical utility of our hospital's clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools. Of the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases. We demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.
Highlights
Mendelian diseases account for a significant number of pediatric disorders
Cohort Description Of the 40 patients, 30, 17, 22, and 25% were patients with primary phenotypes related to multiple congenital anomalies, immunodeficiency, neurological, and mitochondrial disorders, respectively (Table 1; Figure 1, Primary indication)
All patients were under 17 years of age at the time of exome analysis and much younger at the time of clinical presentation (Table 1)
Summary
Mendelian diseases account for a significant number of pediatric disorders. A significant proportion of patients undergo extensive genetic testing including karyotyping, array-based comparative genomic hybridization, Sanger sequencing, and multigene next-generation sequencing panels but still remain undiagnosed [2]. Accurate diagnosis potentially benefits patients and their families by altering clinical management, predicting recurrence risks, providing prognosis, and ending the diagnostic odyssey that is invasive, time consuming and costly. Clinical diagnosis is therapeutic in its own right for the patient/family, as a result of ending the “diagnostic odyssey” – quite apart from the tangible clinical benefits. There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. There are no reports addressing the cost burden associated with genetic tests performed prior to WES
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