Scoring Algorithm‐Based Genomic Testing in Dystonia: A Prospective Validation Study
Michael Zech, Robert Jech, Sylvia Boesch, Matěj Škorvánek, Ján Necpál, Jana Švantnerová, Matias Wagner, Ariane Sadr‐Nabavi, Felix Distelmaier, Martin Krenn, Tereza Serranová, Irena Rektorová, Petra Havránková, Alexandra Mosejová, Iva Příhodová, Jana Šarláková, Kristína Kulcsárová, Olga Ulmanová, Karel Bechyně, Miriam Ostrožovičová, Vladimír Haň, Joaquim Ribeiro Ventosa, Theresa Brunet, Riccardo Berutti, Mohammad Shariati, Ali Shoeibi, Susanne A. Schneider, Alice Kuster, Matthias Baumann, David Weise, Friederike Wilbert, Wibke G. Janzarik, Matthias Eckenweiler, Volker Mall, Bernhard Haslinger, Steffen Berweck, Juliane Winkelmann, Konrad Oexle
Abstract
BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.