CLINICAL EXOME SEQUENCING IN SERBIAN PATIENTS WITH MOVEMENT DISORDERS - SINGLE CENTRE EXPERIENCE

The aim of the study was to analyze the genetic basis of a various range of neurodegenerative disorders manifesting by movement disorders (MD) using next generation sequencing (NGS) clinical exome panel. The study included a total number of 42 cases, 36 unrelated and 3 sibling pairs patients diagnosed with movement disorders, all negative after targeted genetic testing available at Neurology clinic, UCCS, Belgrade, Serbia. In a selection of respondents, preference was given to family cases with the early presentation, patients with a positive family history, or complex MD phenotype. Sequencing of a Clinical exome (CE) panel for 4813 genes with known associated clinical phenotypes was performed on an Illumina MiSeq NGS platform according to the manufacturer's instructions. Sequence variants were analyzed by Illumina's Variant Studio v3 software as well as using previously developed pipeline. Variants analysis and interpretation were based on phenotype gene target approach, literature and databases search, allele frequency, and pathogenicity prediction by in silico software. Causative variants were confirmed by Sanger sequencing. Whenever possible, additional family members were studied for segregation analysis. We identified a likely genetic cause of MD in 5 cases. CE panel analysis revealed 7 different missense and one splice site pathogenic/likely pathogenic variants in 5 genes related to rare neurodegenerative disorders. Detected pathogenic/likely pathogenic variants in the TUBB4A, PANK2, SETX, MFSD8, and ARSA genes have been compatible with the clinical phenotype of the patients. Furthermore, in additional three cases variants in the DCTN1, PDGFRB, and POLG genes have been detected as a possible cause of disease. In the rest of the studied cases, genetic diagnosis remains unclear. These results emphasize the significance of CE panel analysis in elucidating the diagnosis of neurodegenerative diseases manifesting by movement disorders and gave us insight into the complexity of the genetic background of this group of disorders.