Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles

Abstract

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41–76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT. Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2–5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2. All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

Association of ADAM10 gene variants with sporadic Parkinson's disease in Chinese Han population

“…Several studies have suggested that ADAM10 gene is potentially involved in the development of neurodegenerative disorders 26–29 . Though an earlier published negative report indicated the lack of association between ADAM10 and AD, 30 a reasonable explanation for this inconsistency might be based on SNP variations and sample characteristics.…”

A Novel Putative Role of TNK1 in Atherosclerotic Inflammation Implicating the Tyk2/STAT1 Pathway

“…Besides atherosclerosis, TNK1 also participates in several other diseases, such as atypical dementia, Alzheimer's Disease, and colorectal cancer [ 17 – 19 ]. In the trauma-induced intestinal injury and multiorgan failure, TNK1 induces cell apoptosis and the release of proinflammatory factors, IL-6 and TNF- α .…”

Alzheimer’s disease-associatedTM2Dgenes regulate Notch signaling and neuronal function inDrosophila

“…AD is an adult-onset age-dependent disease that worsens over time. While TM2D3 p.P155L has been associated with LOAD (Jakobsdottir et al, 2016) and TM2D3 p.P69L has been recently reported in a proband with EOAD or frontotemporal dementia (Cochran et al, 2019), there is no functional data that directly links this gene to an age-dependent neurological phenotype in any species. To determine if loss of TM2D3 causes an age-dependent phenotype, we first assessed the lifespan of amx D mutant animals.…”

“…This showed that the function of TM2D3 is evolutionarily conserved between flies and humans, and the molecular function of TM2D3 that is relevant to LOAD may also be related to Notch signaling. More recently, another rare missense variant (p.P69L) in this gene has been reported in a proband that fit the diagnostic criteria of EOAD or frontotemporal dementia (Cochran et al, 2019), indicating that other TM2D3 variants may be involved in dementia beyond LOAD.…”