Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Abstract

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

Keywords: blepharospasm; cervical dystonia; dystonia; focal; genetic.

Figure 1

The distribution of the variants for each investigated gene (all patients; n = 121). The autosomal dominant inheritance mode is indicated with dark color, whereas the recessive is indicated with light color. No inheritance data are available for REEP4 (transparent color). Interestingly, the most frequently identified variation in our population was in the SYNE1 gene (Synofzik et al. [19] have already shown that SYNE1 mutations can not only cause pure cerebellar ataxias). Abbreviations: ANO3—anoctamin 3; ATM—ataxia-telangiectasia mutated; ATP7B—ATPase copper transporting beta; C19orf12—chromosome 19 open reading frame 12; CACNA1A—calcium channel, voltage-dependent, P/Q type, alpha-1A subunit; CACNA1B—calcium channel, voltage-dependent, N type, alpha-1B subunit; CIZ1—CIP1-interacting zinc finger protein; COL6A3—collagen, type VI, alpha-3; CP—ceruloplasmin; DRD5—dopamine receptor D5; FTL—ferritin light chain; FUS—fused in sarcoma; GCH1—GTP cyclohydrolase 1; GNAL—guanine nucleotide-binding protein alpha-activating activity polypeptide, olfactory type; KMT2B—lysine-specific methyltransferase 2B; LRRK2—leucine-rich repeat kinase 2; PANK2—pantothenate kinase 2; PRKRA—protein kinase, interferon-inducible double-stranded RNA-dependent activator; RAB12—RAS-associated protein RAB12; REEP4—receptor expression-enhancing protein 4; SGCE—sarcoglycan, epsilon; SPR—sepiapterin reductase; SYNE1—spectrin repeat-containing nuclear envelope protein 1; TH—tyrosine hydroxylase; THAP1—THAP domain-containing protein 1; TOR1A—torsin 1A; TUBB4A—tubulin, beta-4A; VPS16—VPS16 core subunit of corvet and HOPS complexes; VPS41—VPS41 subunit of HOPS complex; WDR45—WD repeat-containing protein 45.