Dóra Csabán1, Anett Illés1, Renáta Bencsik1, Viktor Molnár1, András Gézsi1,Zoltán Grosz1, Tibor Kovács2, Mária Judit Molnár1
1 Institute of Genomic Medicine and Rare Disorders, Semmelweis University
2 Department of Neurology, Semmelweis University
Introduction: Dementias have heterogeneous genetic background, most of them are polygenic disorders, cc 5-10% are monogenic disorders. Due to the next generation sequencing (NGS) technology there are increasing information about its genetic risk factors and monogenic background.
Aim: The aim of our study was to analyze the genetic background of dementia in Hungarian patients. Our cohort was pre-screened for the most common dementia associated genes by Sanger sequencing and C9orf72 hexanucleotid repeat expansions. In subjects without positive results NGS was performed to study all genes which were previously associated with dementia.
Materials and Methods: In our study 95 Hungarian patients with dementia (age of onset < 65 years of age) were analyzed for PSEN1, PSEN2, APP, MAPT, GRN genes by Sanger sequencing. In 54 patients C9orf72 repeat expansion were measured with repeat-primed PCR and 127 neurodegeneration associated gene were analyzed with NGS. The mean age of onset in this cohort was 55.3 ± 8.28 years of age and familiar aggregation was reported in 15 cases.
Results: Single gene analysis detected pathogenic mutation in 5.26% of the cases (PSEN1, PSEN2, APP). Six cases (11.11%) were positive for C9orf72 repeat expansion. NGS detected several heterozygous pathogenic (3.7%) or possibly damaging alterations (16,6%) in GRN, TREM2, ABCA7, c19orf12, EPHA1 genes. The TREM2 gene rare variants as risk factor was present in 2 cases in this cohort,
Conclusion: In dementia, since neurodegenerative disorders are spectrum disorders, NGS can effectively analyze the genetic background of the disease. The identification of rare variants and genetic risk factors may contribute to understand the complex genetic etiology of dementia and stratify the patients for future therapeutic options.
Doctoral School: János Szentágothai Doctoral School of Neurosciences
Program: Clinical Neurosciences
Supervisor: Mária Judit Molnár