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Original research
Clinical impact of whole-genome sequencing in patients with early-onset dementia
  1. Aamira J Huq1,2,3,
  2. Bryony Thompson1,4,
  3. Mark F Bennett5,
  4. Adam Bournazos6,7,
  5. Shobhana Bommireddipalli6,7,
  6. Alexandra Gorelik3,
  7. Joshua Schultz1,
  8. Adrienne Sexton1,
  9. Rebecca Purvis1,
  10. Kirsty West1,
  11. Megan Cotter2,
  12. Giulia Valente2,
  13. Andrew Hughes2,
  14. Moeen Riaz8,
  15. Maie Walsh1,
  16. Sarah Farrand9,
  17. Samantha M Loi9,
  18. Trevor Kilpatrick3,
  19. Amy Brodtmann3,10,11,
  20. David Darby10,12,
  21. Dhamidhu Eratne9,
  22. Mark Walterfang9,
  23. Martin Bruce Delatycki2,
  24. Elsdon Storey1,13,
  25. Michael Fahey14,
  26. Sandra Cooper6,7,
  27. Paul Lacaze8,
  28. Colin L Masters15,
  29. Dennis Velakoulis9,
  30. Melanie Bahlo5,
  31. Paul A James1,
  32. Ingrid Winship1,3
  1. 1Department of Genomic Medicine, Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia
  2. 2Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
  3. 3Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
  4. 4Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
  5. 5Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  6. 6Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia
  7. 7The University of Sydney, Sydney, New South Wales, Australia
  8. 8Public Health and Preventative Medicine, Monash University Faculty of Medicine, Nursing and Health Sciences, Melbourne, Victoria, Australia
  9. 9Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  10. 10Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia
  11. 11Florey Neurosciences Institutes, University of Melbourne, Carlton South, Victoria, Australia
  12. 12Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia
  13. 13Neuroscience, Alfred Health, Melbourne, Victoria, Australia
  14. 14Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia
  15. 15Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Aamira J Huq, Department of Genomic Medicine, The Royal Melbourne Hospital City Campus, Parkville 3050, Victoria, Australia; Aamira.huq{at}


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
  • Neurogenetics
  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.