Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study

摘要

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0-12.0) with 43 of males (55/128), and the median disease duration was 7 months (IQR 1-47). In the whole analysis, the CES diagnostic yield was 55 (70/128). The median test-to-report time was 5 months (IQR 4-7). According to CES indications, the CES diagnostic yields were 81 (21/26) for hyperlipidemia, 75 (6/8) for osteogenesis imperfecta, 64 (25/39) for metabolic disorders, 39 (10/26) for neurological disorders, and 28 (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. GRAPHICS .