• Kostic, Vladimir
• Bergant, Gaber
• Jankovic, Milena
• Peterlin, Borut
• Branković, Marija
• Novakovic, Ivana
• Peric, Stojan
• Maver, Ales
• Petrovic, Igor
• Dragasevic, Natasa
• Dobricic, Valerija
• Marjanovic, Ana
• Svetel, Marina
• Jancic, Jasna

Abstract

<jats:p>The aim of the study was to analyze the genetic basis of a various range ofneurodegenerative disorders manifesting by movement disorders (MD) usingnext generation sequencing (NGS) clinical exome panel. The study included atotal number of 42 cases, 36 unrelated and 3 sibling pairs patientsdiagnosed with movement disorders, all negative after targeted genetictesting available at Neurology clinic, UCCS, Belgrade, Serbia. In aselection of respondents, preference was given to family cases with theearly presentation, patients with a positive family history, or complex MDphenotype. Sequencing of a Clinical exome (CE) panel for 4813 genes withknown associated clinical phenotypes was performed on an Illumina MiSeq NGSplatform according to the manufacturer?s instructions. Sequence variantswere analyzed by Illumina?s Variant Studio v3 software as well as usingpreviously developed pipeline. Variants analysis and interpretation werebased 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. Weidentified a likely genetic cause of MD in 5 cases. CE panel analysisrevealed 7 different missense and one splice site pathogenic/likelypathogenic 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 ofthe patients. Furthermore, in additional three cases variants in the DCTN1,PDGFRB, and POLG genes have been detected as a possible cause of disease. Inthe rest of the studied cases, genetic diagnosis remains unclear. Theseresults emphasize the significance of CE panel analysis in elucidating thediagnosis of neurodegenerative diseases manifesting by movement disordersand gave us insight into the complexity of the genetic background of thisgroup of disorders.</jats:p>

Topics

• molecular dynamics