Basic Science and Pathogenesis

Abstract

BACKGROUND: Early-onset dementia (EOD) is a uncommon form of dementia that afflicts people before age 65. Only a few studies analyzing the genetics of EOD have been performed in Thai population. EOD remains a challenge due to the diverse genetic and clinical heterogeneity of these diseases. The aim of this study was to investigate the genetic spectrum of Thai EOD and those with familial history of dementia. METHOD: 150 subjects with EOD AND 18 individuals with familial dementia were recruited. Targeted next generation (NGS) analyses were performed to screen 38 genes associated with dementia. RESULT: Subject characteristics were demonstrated in table 1. Fifteen had pathogenic variants. Among pathogenic (47%) and likely pathogenic (53%) variants, 5 (33.33%) were in PSEN1 (c.417G>T, p.Met139Ile), (c.344A>G, p.Tyr115Cys), (c.817G>A, p.Glu273Lys), (c.817G>A, p.Glu273Lys), (c.485T>C, p.Ile162Thr)); 2 (13.33%) in CSF1R (c.704T>G, p.Val235Gly), (c.2522A>G, p.Tyr841Cys); 1(6.67%) each in ABCA7 (c.5571-1G>C, p.?), SNCB (c.372G>A, p.Gln124=), SORL1 (c.2212G>A, p.Gly738Arg), APP (c.2149G>A, p.Val717Ile), VAPB (c.301G>T, p.Asp101Tyr), GRN (c.276C>A, p.Cys92Ter), SOD1 (c.143T>C, p.Val48Ala), and NOTCH3 (c.1630C>T, p.Arg544Cys). Among these, the PSEN1 variant c.817G>A (p.Glu273Lys) had not previously been reported. 61 had variants of uncertain significance (VUS). Graphs 1-3 showed results of NGS for dementia in the whole cohort, in those with pathogenic variants, and in those with VUS. CONCLUSION: Our study demonstrated the genetic spectrum of EOD and familial dementia in Thai patients. The utilization of next-generation sequencing could help deciphering the genetic causes of Alzheimer's disease. The genetic testing of known causal genes in EOD patients can help make a precise diagnosis. We acknowledged Thailand Science Research and Innovation for supporting this study.