• Kostic, Vladimir
• Stefanova, Elka
• Dobricic, Valerija
• Stevic, Zorica
• Bergant, Gaber
• Jankovic, Milena
• Peterlin, Borut
• Branković, Marija
• Novakovic, Ivana
• Marjanovic, Ana
• Mandic, Gorana
• Maver, Ales

Abstract

<jats:p>As life span rises, dementia has become a growing public health issue.According to current estimates, almost 50 million people worldwide havedementia, and the number is expected to grow. Next generation sequencing(NGS) methods have helped significantly with identifying causative genevariants related to various cognitive disorders. Our study aimed to analyzethe genetic basis of cognitive disorders using NGS clinical exome panel. Thestudy included a total number of 15 unrelated cases diagnosed with cognitivedisorders, all negative after standard targeted genetic testing wasperformed (available at Neurology Clinic, UCCS, Belgrade, Serbia).Preference was given to familial cases with early presentation or complexphenotype. Sequencing of a clinical exome (CE) panel for 4813 genes withknown associated clinical phenotypes was performed using TruSight Onesequencing panel on an Illumina MiSeq NGS platform according to themanufacturer?s instructions (Illumina, San Diego, CA, USA). Variants wereanalyzed with Illumina Variant Studio v3 software provided by Illumina aswell as a previously developed pipeline. Variants analysis andinterpretation were based on phenotype gene target approach, literature anddatabases search, allele frequency, and pathogenicity prediction by insilico software. All causative variants were confirmed by Sanger sequencing.Whenever possible, additional family members were studied for segregationanalysis. CE panel analysis revealed a likely genetic cause in fourpatients. We have detected two missense heterozygous pathogenic variants inthe PSEN1 gene in one patient each and homozygous nonsense pathogenicvariant in the OPTN gene in two more patients. Detected pathogenic variantsare in line with the clinical phenotype of our patients. In the rest of the11 cases, genetic diagnosis remains unclear. The results of our studyemphasize the significance of CE panel analysis in establishing a diagnosisfor patients with dementia. Furthermore, give us insight into the complexityof the genetic background of this group of disorders.</jats:p>

Topics

• impedance spectroscopy