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

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.

Figure 1. ES and Multigene Panel Testing in 1,411 Patients Yields a Diagnosis in 10% of the Cases

(A) Detection rate of causal variants and variants of unknown clinical significance (VUS) per gene panel (expressed in percentages). (B) Overview of the most frequently implicated genes across all gene panels ranked according to the burden of (likely) pathogenic variants. (C) Distribution of causal variant type. (D) Inheritance pattern associated with the molecular diagnoses.

Figure 2. Novel APP Likely Pathogenic Missense Variant (p.[Asn698Asp], Ghent Variant), Associated With Cerebral Amyloid Angiopathy

(A and B) Brain MRI of our patient showing signs of extensive microangiopathy with diffuse confluent leukoencephalopathy (A1) lacunar infarctions (A1, indicated by arrows) and involvement of basal ganglia, pons (A2), and right cerebral peduncle (fluid-attenuated inversion recovery (FLAIR) imaging) and several cerebral microbleeds (susceptibility weighted imaging (SWI) (B1-2, indicated by arrows). (C) Pedigree of the patient in which the novel variant was identified. The proband is indicated with an arrow. (D) Results of patient CSF analysis and reference values for total and phosphorylated tau, Aβ₄₂, and the ratio of Aβ₄₂/Aβ₄₀. (E) Schematic of the transmembrane amyloid precursor protein. The arrows indicate the sites of secretase activity. The amino acid sequence of the Aβ domain is depicted, together with the pathogenic variants that have been identified in this region. The novel Ghent variant (p.[Asn698Asp]), with a CADD score of 25.6, is depicted in bold. The asparagine residue is moderately conserved but is located in a highly conserved region.