In this study, we conducted a comprehensive analysis of high and moderate genetic risk factors in an Austrian cohort of early-onset dementia (EOD).
For this, we performed extensive genetic screening using WES, copy number variation (CNV) analysis and C9orf72 repeat-primed PCR-analysis. We identified 12 patients (20%) with high penetrant risk variants whom we defined as “carriers of variants relevant for diagnostics” (these include pathogenic variants in APP, MAPT, PSEN1, GRN and the APOE4/4 genotype). In this group, we also included APOE4 homozygotes, as their lifetime risk for developing dementia or cognitive impairment is considerably high, with estimates ranging from 30–50% [49] and up to over 80% in 80-year-olds [11]. However, for most of our patients (80%), we could not find highly penetrant mutations, thus leaving the overwhelming part of our patients “genetically unexplained”. This is in accordance with previous WES studies in EOD, where a diagnostic yield of only 16–30% has been observed [6–9]. Variants conferring a high lifetime risk are generally considered “diagnostically relevant”, and patients should be informed. However, there is uncertainty and lack of clear guidance with regards to what penetrance, respectively, lifetime risk, a variant should be categorized as relevant for patient counseling. Nevertheless, classifying variants as ‘diagnostically relevant’ is an important category and will become more and more relevant, in view of emerging disease modifying therapies and potentially other actionable choices with regards to family planning and lifestyle choices.
Additionally, we describe patients with rare but established risk variants (TREM2, APOE4 heterozygotes) and rare variants in known risk genes (ABCA7 and SORL1), which have not yet been described in the literature (carriers of well-established and potential new risk variants). Although no reliable assumption about their pathogenicity can be made at this stage, it is plausible that some of them could confer increased risk. Testing these variants in larger case-control cohorts is necessary to answer this question. However, it should be mentioned that a reliable statement can only be made if variants are tested in their population-specific cohorts, such as SORL1-p.G1536S, which is almost exclusively present in the Ashkenazi Jewish population.
As expected, carriers of mutations in autosomal dominant genes showed the earliest age of onset and the strongest familial background compared to the other patients. 70% (n = 5/7) of them had Goldman scores from 1–3, but only 31% (n = 5/16) of “risk variant carriers” and 16% (n = 5/32) of “no variant carriers” scored in this range. The weaker familial background in these groups may indicate that oligogenic inheritance mechanisms may play a more important role in these patients, as previously suggested for AD [50–53]. In this respect, it is interesting to highlight patient EOD-2, whose disease onset was at 44 years of age, the second youngest in the entire cohort. He carried three disease variants; the likely causal variant MAPT-p.(P636L), the established risk variant TREM2-p.(R62C) and an APOE4/3 genotype. It is tempting to speculate that additive effects may contribute to this exceptionally early disease onset.
Finally, in a more exploratory approach, we aimed to search for potential new risk genes. For this purpose, we compiled a list of 564 genes that were previously considered genetically or functionally related to neurodegeneration (Supplementary Table 2). We then prioritized those genes in which variants were found in at least two patients or strongly associated with pathways involved in dementia pathogenesis. We nominate five genes (DCTN1, JIP3/MAPK8IP3, LRRK2, BACE1 and VPS13C) as promising candidates. However, it must be clearly stated that no statistical evidence can be provided for any of these five genes. A major problem in identifying new disease genes is the tremendous number of variants and variant combinations in any given individual. At best, statistical proof is possible when the same variant or variant combinations are found repeatedly in different patients. Assuming that new potentially pathogenic variants, as described here, rarely occur, appropriately large cohorts are needed to have a chance of a second finding. We believe that one way of addressing this problem is to provide unabridged sequencing results along with clinical information to the scientific community. Our approach is to deposit all of our exome data in the European Genome-Phenome Archive (EGA), making it accessible to all qualified users. Thereby, we hope to increase the chance that the same gene/variant-hit might be found independently in other well-defined EOD patients, thus confirming new genetic risk variants or variant combinations. We acknowledge that no definite conclusions on pathogenicity of our proposed candidate genes can be drawn from the present study, and we emphasize that the nomination of these candidate genes is intended as a suggestion and impetus for further research.
Altogether, we present 60 EOD patients that have been extensively studied, both genetically and clinically. We show that in only 20% the underlying disease cause can be explained with high probability by high-penetrant mutations (PSEN1, MAPT, APP, and GRN) and homozygosity of the APOE4/4 genotype These variants are relevant for supporting the diagnosis, patient counseling and, eventually, also for future therapeutic interventions. Carrier status of such genotypes also correlates with early disease onset and, in the case of autosomal dominant variants, the strongest family history in this cohort.
In addition, we present potentially novel risk variants in established and new genes. Our cohort's clinical and genetic data will be made publicly available to allow other researchers to perform an independent analysis. Thus, we hope that potentially new genetic risk variants can be confirmed.