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.

Keywords: Alzheimer disease; frontotemporal dementia.

Figure 1.

Summary of genomic analysis results for 32 patients with early-onset or familial dementia. Pathogenic variants were observed in APP (x2), C9orf72 (x3), and MAPT (x3). A likely pathogenic variant was observed in CSF1R. Five patients were APOE ε4 homozygous, with four of these patients also harboring additional risk variants in AKAP9, GBA, PLD3, and TREM2. Two patients were APOE ε4 heterozygous and had additional risk variants in SORL1 and TREM2. Two patients had variants of uncertain significance (VUS) in MAPT and NOTCH3. For six patients, the only returnable finding was APOE ε4 heterozygosity. Eight patients had no returnable findings.

Figure 2.

Neuroimaging findings in a CSF1R variant carrier. (A,B) Frontal-predominant, mildly asymmetric (R > L) white matter hyperintensities on axial FLAIR images. (C,D) Global cerebral atrophy on coronal and axial MPRAGE images. Radiological orientation with patient's R side displayed on L.

Figure 3.

Molecular modeling of the effect of the M105T variant on SORL1. (A) Conservation analysis of the SORL1 gene sequence was performed across open reading frame sequences of 135 species. Scores at each codon were assessed with 100% conservation receiving a score of 1, with addition of a score for codon selection (score of 0 if dN-dS of site is below mean, 0.25 for sites with values above the mean to one standard deviation above the mean, 0.5 for sites greater than one standard deviation but below two standard deviations, 1 for sites greater than two standard deviations). A score of 2 is maximal, suggesting an amino acid that is 100% conserved with codon wobble indicative of a high selection rate at the position. The values were then placed on a 21-codon sliding window (combining values for 10 codons before and after each position) to identify conserved motifs within the gene. (B) Model of SORL1 protein (assessed with YASARA2). Colors are based on 135 species alignments fed into ConSurf such that colors indicate (gray) not conserved, (yellow) conserved hydrophobic, (red) conserved polar acidic, (blue) conserved polar basic, (green) conserved hydrophilic. Note that the M105T variant leads to a predicted gain of a PLK1 kinase target site in SORL1.

Figure 4.

Multiple variants in neurodegeneration-associated genes are often observed in early-onset dementia, with a critical role for rare variants acting in combination with APOE ε4. Note that for all panels, ε4/ε* indicates either ε4/ε3 or ε4/ε2 (mostly ε4/ε3). Also for all panels, cases N = 31 (32 probands excluding 1 sibling from an affected sibling pair), controls N = 542, and unaffected family members of cases N = 29. All comparisons are by exact conditional Cochran–Armitage trend test unless otherwise specified. (A) Qualifying candidate alleles associated with neurodegeneration (see text for criteria) are highly enriched in cases (P = 9.2 × 10⁻¹²). Unaffected family members are intermediate between cases and controls (P = 0.01 vs. cases, P = 0.001 vs. controls). (B) Presence of APOE ε4 alone, in the absence of any other qualifying variants, is not enriched in cases (P = 0.57). Unaffected family members show a significantly different APOE ε4 allele distribution from controls (P = 0.026) but not cases (P = 0.97). (C) Presence of APOE ε4 along with at least one qualifying rare variant (including Mendelian variants) is highly enriched in cases (P = 1.0 × 10⁻⁹). Enrichment over controls is also observed in unaffected family members (P = 5.6 × 10⁻⁴), but unaffected family members are not statistically distinguishable from cases (P = 0.055). (D) Presence of APOE ε4 along with at least one qualifying rare variant (excluding Mendelian variants) is highly enriched in cases (P = 1.4 × 10⁻⁶) and also enriched in unaffected family members (P = 5.6 × 10⁻⁴), but unaffected family members are not distinguishable from cases (P = 0.84). The odds ratio for presence of one APOE ε4 allele along with one qualifying rare variant in cases versus controls is 5.5 (P = 0.01 by Fisher's exact test, 95% CI 1.2–19.3). The odds ratio for presence of two APOE ε4 alleles along with one qualifying rare variant in cases versus controls is 39.1 (P = 9.8 × 10⁻⁵ by Fisher's exact test, 95% CI 5.3–447.5).