Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic

Abstract

Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing-WES; whole-genome sequencing-WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.

Keywords: ataxia; genetics; long-read sequencing; parkinsonism; whole-exome sequencing.

Figure 1

Main results of the study. Green: Positive results (diagnostic yield) reached 27% (22 out of 82 probands) (left), of whom 26% (21) with pathogenic or likely pathogenic variants, and 1% (1) with strong-gene VUS candidate (green filled circle) (right). Blue: differently, 58% (71) of patients resulted negative, and 2.4% patients (2) resulted as VUS-non strong candidates (left).

Figure 2

Flowchart of the ideal diagnostic algorithm for patients presenting in the movement disorders genetic clinic. Based on the family history, brain imaging, and clinical phenotype; after having ruled out the most common and reversible causes, patients undergo genetic testing. First, commercial panels or sequencing of single genes is recommended, based on costs and patients’ availabilities. Then, if negative or of uncertain significance, testing through research avenues is recommended. SCAs, spinocerebellar ataxia; RFC1, replication factor C subunit 1—gene of cerebellar ataxia, neuropathy and vestibular areflexia—CANVAS; FGF14, fibroblast growth factor 14—gene of SCA27B; GP2, Global Parkinson’s Genetics Program; WES, whole-exome sequencing; WGS, whole-genome sequencing.