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 Darby; Dhamidhu 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

doi:10.1136/jnnp-2021-328146

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

J Neurol Neurosurg Psychiatry. 2022 Jul 29:jnnp-2021-328146. doi: 10.1136/jnnp-2021-328146. Online ahead of print.

Authors

Aamira J Huq^{1

2

3}, Bryony Thompson^{4

5}, Mark F Bennett⁶, Adam Bournazos^{7

8}, Shobhana Bommireddipalli^{7

8}, Alexandra Gorelik³, Joshua Schultz⁴, Adrienne Sexton⁴, Rebecca Purvis⁴, Kirsty West⁴, Megan Cotter², Giulia Valente², Andrew Hughes², Moeen Riaz⁹, Maie Walsh⁴, Sarah Farrand¹⁰, Samantha M Loi¹⁰, Trevor Kilpatrick³, Amy Brodtmann^{3

11

12}, David Darby^{11

13}, Dhamidhu Eratne¹⁰, Mark Walterfang¹⁰, Martin Bruce Delatycki², Elsdon Storey^{4

14}, Michael Fahey¹⁵, Sandra Cooper^{7

8}, Paul Lacaze⁹, Colin L Masters¹⁶, Dennis Velakoulis¹⁰, Melanie Bahlo⁶, Paul A James⁴, Ingrid Winship^{4

3}

Affiliations

¹ Department of Genomic Medicine, Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia [email protected].
² Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
³ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
⁴ Department of Genomic Medicine, Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia.
⁵ Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁶ Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁷ Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁸ The University of Sydney, Sydney, New South Wales, Australia.
⁹ Public Health and Preventative Medicine, Monash University Faculty of Medicine, Nursing and Health Sciences, Melbourne, Victoria, Australia.
¹⁰ Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹¹ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia.
¹² Florey Neurosciences Institutes, University of Melbourne, Carlton South, Victoria, Australia.
¹³ Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia.
¹⁴ Neuroscience, Alfred Health, Melbourne, Victoria, Australia.
¹⁵ Royal Melbourne Hospital City Campus, Parkville, Victoria, Australia.
¹⁶ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.

PMID: 35906014
DOI: 10.1136/jnnp-2021-328146

Abstract

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.

Keywords: 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.