Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders

Nika Schuermans; Hannah Verdin; Jody Ghijsels; Madeleine Hellemans; Elke Debackere; Elke Bogaert; Sofie Symoens; Leslie Naesens; Elien Lecomte; David Crosiers; Bruno Bergmans; Kristof Verhoeven; Bruce Poppe; Guy Laureys; Sarah Herdewyn; Tim Van Langenhove; Patrick Santens; Jan L De Bleecker; Dimitri Hemelsoet; Bart Dermaut; for Program for Undiagnosed Rare Diseases (UD-PrOZA)

doi:10.1212/NXG.0000000000200071

Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders

Neurol Genet. 2023 Apr 26;9(3):e200071. doi: 10.1212/NXG.0000000000200071. eCollection 2023 Jun.

Authors

Nika Schuermans¹, Hannah Verdin¹, Jody Ghijsels¹, Madeleine Hellemans¹, Elke Debackere¹, Elke Bogaert¹, Sofie Symoens¹, Leslie Naesens¹, Elien Lecomte¹, David Crosiers¹, Bruno Bergmans¹, Kristof Verhoeven¹, Bruce Poppe¹, Guy Laureys¹, Sarah Herdewyn¹, Tim Van Langenhove¹, Patrick Santens¹, Jan L De Bleecker¹, Dimitri Hemelsoet¹, Bart Dermaut¹; for Program for Undiagnosed Rare Diseases (UD-PrOZA)

Affiliation

¹ Center for Medical Genetics (N.S., H.V., J.G., E.D., E.B., S.S., B.P., B.D.), Ghent University Hospital; Department of Biomolecular Medicine (N.S., H.V., J.G., M.H., E.D., E.B., S.S., B.P., B.D.), Faculty of Medicine and Health Sciences, Ghent University; Department of Internal Medicine and Pediatrics (L.N.), Ghent University; Primary Immunodeficiency Research Lab (L.N.), Jeffrey Modell Diagnosis and Research Center, Ghent University Hospital; Department of Neurology (E.L.), O.L.V. Lourdes Hospital, Waregem; Department of Neurology (D.C.), Antwerp University Hospital UZA; Translational Neurosciences (D.C.), Faculty of Medicine and Health Sciences, University of Antwerp; Department of Neurology (B.B., K.V.), AZ Sint-Jan, Bruges; and Department of Neurology (B.B., G.L., S.H., T.V.L., P.S., J.L.D.B., D.H.), Ghent University Hospital, Belgium.

Abstract

Background and objectives: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders.

Methods: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance.

Results: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique.

Discussion: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.