Increased diagnostic yield from negative whole genome-slice panels using automated reanalysis

Seth I. Berger, Children's National Rare Disease Institute, Division of Genetics and Metabolism, Washington, DC, USA.
Georgia Pitsava, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Andrea J. Cohen, Children's National Rare Disease Institute, Division of Genetics and Metabolism, Washington, DC, USA.
Emmanuèle C. Délot, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Jonathan LoTempio, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Erin Hallie Andrew, Children's National Rare Disease Institute, Division of Genetics and Metabolism, Washington, DC, USA.
Gloria Mas Martin, Translational Research, Invitae Corporation, San Francisco, California, USA.
Sofia Marmolejos, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Jessica Albert, Molecular Diagnostics Laboratories, Children's National Hospital, Washington, DC, USA.
Beatrix Meltzer, Molecular Diagnostics Laboratories, Children's National Hospital, Washington, DC, USA.
Jamie Fraser, Children's National Rare Disease Institute, Division of Genetics and Metabolism, Washington, DC, USA.
Debra S. Regier, Children's National Rare Disease Institute, Division of Genetics and Metabolism, Washington, DC, USA.
Amanda H. Kahn-Kirby, Translational Research, Invitae Corporation, San Francisco, California, USA.
Erica Smith, Translational Research, Invitae Corporation, San Francisco, California, USA.
Susan Knoblach, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Arthur Ko, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
Vincent A. Fusaro, Translational Research, Invitae Corporation, San Francisco, California, USA.
Eric Vilain, Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.

Document Type

Journal Article

Publication Date

5-17-2023

Journal

Clinical genetics

DOI

10.1111/cge.14360

Keywords

panel testing; whole genome sequencing

Abstract

We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.

Department

Pediatrics

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