Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study

Zech M, Jech R, Boesch S, Škorvánek M, Necpál J, Švantnerová J, Wagner M, Sadr-Nabavi A, Distelmaier F, Krenn M, Serranová T, Rektorová I, Havránková P, Mosejová A, Příhodová I, Šarláková J, Kulcsarová K, Ulmanová O, Bechyně K, Ostrozovičová M, Haň V, Ventosa JR, Brunet T, Berutti R, Shariati M, Shoeibi A, Schneider SA, Kuster A, Baumann M, Weise D, Wilbert F, Janzarik WG, Eckenweiler M, Mall V, Haslinger B, Berweck S, Winkelmann J, Oexle K.

Mov Disord.2021 May 5. doi: 10.1002/mds.28614. Epub ahead of print. PMID: 33949708.


7 May 2021

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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.

Keywords: diagnostic yield; dystonia; exome sequencing; prediction; rare disease; scoring algorithm.

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