Background In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation.
Methods WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer’s disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD.
Results Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk.
Discussion WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.
- Early Onset Dementia
- Dementia Genetics
- Medical Genetics
- Clinical Genetics
- American College of Medical Genetics and Genomics
- Whole Genome Sequencing
- Structural Variant analysis
- Short Tandem Repeat Analysis
Data availability statement
Data are available upon reasonable request.
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Contributors AJH—conception and study design, obtaining ethics and governance approval, data analysis and writing of the manuscript. BT—WGS analysis and manuscript review. MFB and MB—STR analysis, PRS analysis, assistance with SV analysis and manuscript review. AB, SB and SC—mRNA analysis and manuscript review. AG—statistical analysis and manuscript review. JS, AS, RP, KW, MC and GV—pretest patient counselling and manuscript review. AH, MW, SF, SML, TK, AB, DD, DE, MW, MBD, ES, MF and DV—clinical workup of patients referred to the study and manuscript review. MR—data management and manuscript review. PL, CLM, PAJ and IW—assistance and supervision with study conception, design and manuscript writing. AJH acts as guarantor.
Funding AJH was supported by the Commonwealth Research Training Program Scholarship, Australia (University of Melbourne reference number 96756) and the Yulgilbar Alzheimer Research Program. MFB was supported by a Taking Flight award from CURE Epilepsy. MB was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1102971). This work was made possible through the Yulgilbar Alzheimer Research Program, the Victorian Government’s Operational Infrastructure Support Program and Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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