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Title: Clinical impact of whole-genome sequencing in patients with early-onset dementia.
Austin Authors: Huq, Aamira J;Thompson, Bryony;Bennett, Mark F ;Bournazos, Adam;Bommireddipalli, Shobhana;Gorelik, Alexandra;Schultz, Joshua;Sexton, Adrienne;Purvis, Rebecca;West, Kirsty;Cotter, Megan ;Valente, Giulia M ;Hughes, Andrew J ;Riaz, Moeen;Walsh, Maie;Farrand, Sarah;Loi, Samantha M;Kilpatrick, Trevor;Brodtmann, Amy ;Darby, David G;Eratne, Dhamidhu;Walterfang, Mark;Delatycki, Martin B ;Storey, Elsdon;Fahey, Michael;Cooper, Sandra;Lacaze, Paul;Masters, Colin L ;Velakoulis, Dennis;Bahlo, Melanie;James, Paul A;Winship, Ingrid
Affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia..
Department of Genomic Medicine, Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia..
Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia..
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia..
Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia..
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia..
The University of Sydney, Sydney, New South Wales, Australia..
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia..
Clinical Genetics
Public Health and Preventative Medicine, Monash University Faculty of Medicine, Nursing and Health Sciences, Melbourne, Victoria, Australia..
Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia..
The Florey Institute of Neuroscience and Mental Health
Florey Neurosciences Institutes, University of Melbourne, Carlton South, Victoria, Australia..
Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia..
Neuroscience, Alfred Health, Melbourne, Victoria, Australia..
Issue Date: 29-Jul-2022 2022
Publication information: Journal of neurology, neurosurgery, and psychiatry 2022; online first: 29 July
Abstract: 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. 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. 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. 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.
DOI: 10.1136/jnnp-2021-328146
PubMed URL: 35906014
PubMed URL:
Type: Journal Article
Subjects: American College of Medical Genetics and Genomics
Clinical Genetics
Dementia Genetics
Early Onset Dementia
Medical Genetics
Short Tandem Repeat Analysis
Structural Variant analysis
Whole Genome Sequencing
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