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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

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Abstract

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.

Graphic abstract

Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients’ subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0).

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Availability of data and material

Anonymized patient data are available for use in collaborative studies to researchers upon reasonable request. Data will be provided following the review and approval of a research proposal (including a statistical analysis plan) and the completion of a data-sharing agreement. Responses to the request for the raw data will be judged by the IRB of the University Hospital of Nancy.

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Not applicable.

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Funding

INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE) and University Hospital of Nancy.

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J-PM: conceptualization, validation, formal analysis, investigation, writing—original draft, writing—review and editing; AW: conceptualization; validation; formal analysis; investigation; writing—original draft; writing—review and editing; supervision; CC: software, resources, writing—review and editing; J-MR: investigation; writing—review and editing; FN: software, resources, writing—review and editing; J-LG: methodology, software, resources, writing—review & editing, supervision; FF: conceptualization, methodology, formal analysis, investigation, writing—original draft, writing—review and editing, supervision; AO: conceptualization, methodology, software, formal analysis, resources, data curation, writing—review & editing, supervision.

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Correspondence to Abderrahim Oussalah.

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The authors who have taken part in this study declare that they do not have anything to disclose regarding conflicts of interest concerning this manuscript.

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439_2021_2358_MOESM5_ESM.pptx

Supplemental Figure S1. A) Venn diagram illustrating the distribution of the 82 patients with at least one genetic variant (PPTX 1049 kb)

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Mergnac, JP., Wiedemann, A., Chery, C. et al. 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. Hum Genet 141, 1269–1278 (2022). https://doi.org/10.1007/s00439-021-02358-0

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  • DOI: https://doi.org/10.1007/s00439-021-02358-0

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