Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing
Authors: Thomsen Mirja , Ott Fabian , Loens Sebastian , Kilic-Berkmen Gamze , Tan Ai Huey , Lim Shen-Yang , Lohmann Ebba , Schröder Kaja M. , Ipsen Lea , Nothacker Lena A. , Welzel Linn , Rudnik Alexandra S. , Hinrichs Frauke , Odorfer Thorsten , Zeuner Kirsten E. , Schumann Friederike , Kühn Andrea A. , Zittel Simone , Moeller Marius , Pfister Robert , Kamm Christoph , Lang Anthony E. , Tay Yi Wen , Vidailhet Marie , Roze Emmanuel , Perlmutter Joel S. , Feuerstein Jeanne S. , Fung Victor S. C. , Chang Florence , Barbano Richard L. , Bellows Steven , Wagle Shukla Aparna A. , Espay Alberto J. , LeDoux Mark S. , Berman Brian D. , Reich Stephen , Deik Andres , Franke Andre , Wittig Michael , Franzenburg Sören , Volkmann Jens , Brüggemann Norbert , Jinnah H. A. , Bäumer Tobias , Klein Christine , Busch Hauke , Lohmann Katja 
Published: December 2024

Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (∼25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex.

To comprehensively unravel dystonia’s genetic spectrum, we performed exome sequencing on 1,924 dystonia patients [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based on two dystonia registries (DysTract and the Dystonia Coalition). Further, 72 additional patients of Asian ethnicity, mainly from Malaysia, were also included. We prioritized patients with negative genetic prescreening, early AAO, positive family history, and multisite involvement of dystonia. Rare variants in genes previously linked to dystonia (n=405) were examined. Variants were confirmed via Sanger sequencing, and segregation analysis was performed when possible.

We identified 137 distinct likely pathogenic or pathogenic variants (according to ACMG criteria) across 51 genes in 163/1,924 patients [42.9% male, 85.9% White, 68.7% isolated dystonia, median AAO 19 years]. This included 153/1,895 index patients, resulting in a diagnostic yield of 8.1%. Notably, 77/137 (56.2%) of these variants were novel, with recurrent variants inEIF2AK2,VPS16,KCNMA1, andSLC2A1, and novel variant types such as two splice site variants inKMT2B, supported by functional evidence. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes includedVPS16,THAP1,GCH1,SGCE,GNAL, andKMT2B.Presumably pathogenic variants in less well-established dystonia genes were also found, includingKCNMA1,KIF1A, andZMYND11.At least six variants (inADCY5,GNB1,IR2BPL, KCNN2,KMT2B, andVPS16) occurredde novo,supporting pathogenicity. ROC curve analysis indicated that AAO and the presence of generalized dystonia were the strongest predictors of a genetic diagnosis, with diagnostic yields of 28.6% in patients with generalized dystonia and 20.4% in those with AAO < 30 years.

This study provides a comprehensive examination of the genetic landscape of dystonia, revealing valuable insights into the frequency of dystonia-linked genes and their associated phenotypes. It underscores the utility of exome sequencing in establishing diagnoses within this heterogeneous condition. Despite prescreening, presumably pathogenic variants were identified in almost 10% of patients. Our findings reaffirm several dystonia candidate genes and expand the phenotypic spectrum of some of these genes to include prominent, sometimes isolated dystonia.