Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights

Abstract

Background: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations.

Methods: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings.

Results: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis.

Conclusions: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

Keywords: Gene Ontology; gene expression profiling; genetics, medical; nervous system diseases; neurodegenerative diseases.

Figure 1

The classification and the characterisation of the 42 Turkish dystonia families based on the genetic findings. The chart indicates (A) the classification of the families based on the genetic findings, (B) the clinical distribution of the families in the diagnostic group and (C) the variant distribution in the diagnostic group.

Figure 2

The prioritised pathways associated with dystonia. This figure illustrates the prioritised pathways associated with dystonia based on the findings of our study as well as the findings from previous studies. Those pathways include (A) the endosomal-lysosomal pathway involving AOPEP, VPS16, VPS41 and VPS11 genes, (B) the purine pathway involving IMPDH2, HPRT1 and PNP genes, (C) the cell-cycle pathway including THAP1 and MCM4 genes, (D) the transcriptional regulation pathway including TAF1 and CCNT1 genes. In green rectangles the known dystonia-associated genes, in yellow rectangles candidate genes identified in our study have been shown. HOPS, the homotypic fusion and protein sorting complex; TF, transcription binding factor.