Next Generation Sequencing analysis of late‐onset dementia patients with a strong family history

Background Next‐generation sequencing (NGS) techniques allow for efficient screening of potentially pathogenic variants by using gene panels that target the genes known to underlie neurodegenerative dementias. Most NGS studies are focused on cases with early‐onset disease, which have a higher genetic burden. The objective of this study is to identify known and/or novel rare variants in major candidate genes associated with neurodegenerative dementias in cases with a strong family history, including patients with late‐onset disease. Method We studied 53 patients (25 early‐ and 28 late‐onset) with a strong family history of dementia (Goldman scale 1 and 2) and phenotypes including dementia of the Alzheimer type (DAT), frontotemporal variants (FTD) and Lewy body type dementia. Presence of the C9Orf72 hexanucleotide repeat expansion had been ruled out and all cases had plasma progranulin levels within the normal range. The NGS panel included 20 genes. Variants identified were reviewed in genomic databases and analyzed for potential pathogenicity using prediction programs. Segregation was evaluated in available siblings. Result Potentially pathogenic mutations (CADD >20 and/or M‐CAP > 0.025) were found in 20 cases (38%, 11 early‐onset and 9 late‐onset), with two cases carrying mutations in two different genes. We detected known pathogenic mutations in two cases with the SQSTM1 P392L variant, manifesting as bv‐FTD and Paget disease. Six cases had non‐described variants in the PSEN1, ADAM10, SORL1, UBQLN2, and TIROBP genes that were likely disease‐related, as further supported by segregation patterns. We also found rare, potentially pathogenic variants in the SORL1, SQSTM1, and FUS genes in four cases. Finally, ten cases carried variants of unknown‐impact in the following genes: MAPT, CSF1R, ADAM10, SORL1, and SERPINI1. In the late‐onset cases, frontotemporal phenotypes were more likely to have positive results and the potentially pathogenic variants were found in the PSEN1, ADAM10, SQSTM1, FUS, and CSF1R genes. Conclusion It is worthwhile to screen for the genetic causes of the disease in cases with late‐onset dementia if there is a strong family history. Positive results are more likely obtained in frontotemporal phenotypes.