Clinical impact of whole-genome sequencing in patients with early-onset dementia

Aamira J. Huq, Bryony Thompson, Mark F. Bennett, Adam Bournazos, Shobhana Bommireddipalli, Alexandra Gorelik, Joshua Schultz, Adrienne Sexton, Rebecca Purvis, Kirsty West, Megan Cotter, Giulia Valente, Andrew Hughes, Moeen Riaz, Maie Walsh, Sarah Farrand, Samantha M. Loi, Trevor Kilpatrick, Amy Brodtmann, David DarbyDhamidhu Eratne, Mark Walterfang, Martin Bruce Delatycki, Elsdon Storey, Michael Fahey, Sandra Cooper, Paul Lacaze, Colin L. Masters, Dennis Velakoulis, Melanie Bahlo, Paul A. James, Ingrid Winship

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4 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1181-1189
Number of pages9
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number11
Publication statusPublished - Nov 2022


  • American College of Medical Genetics and Genomics
  • Clinical Genetics
  • Dementia Genetics
  • Early Onset Dementia
  • Medical Genetics
  • Neurogenetics
  • Short Tandem Repeat Analysis
  • Structural Variant analysis
  • Whole Genome Sequencing

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