Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

William L. Macken, Micol Falabella, Caroline McKittrick, Chiara Pizzamiglio, Rebecca Ellmers, Kelly Eggleton, Cathy E. Woodward, Yogen Patel, Robyn Labrum, Rahul Phadke, Mary M. Reilly, Catherine DeVile, Anna Sarkozy, Emma Footitt, James Davison, Shamima Rahman, Henry Houlden, Enrico Bugiardini, Rosaline Quinlivan, Michael G. Hanna, Jana Vandrovcova () and Robert D. S. Pitceathly ()
Additional contact information
William L. Macken: UCL Queen Square Institute of Neurology
Micol Falabella: UCL Queen Square Institute of Neurology
Caroline McKittrick: UCL Queen Square Institute of Neurology
Chiara Pizzamiglio: UCL Queen Square Institute of Neurology
Rebecca Ellmers: North Thames Genomic Laboratory Hub
Kelly Eggleton: North Thames Genomic Laboratory Hub
Cathy E. Woodward: The National Hospital for Neurology and Neurosurgery
Yogen Patel: North Thames Genomic Laboratory Hub
Robyn Labrum: The National Hospital for Neurology and Neurosurgery
Rahul Phadke: Great Ormond Street Hospital for Children NHS Foundation Trust
Mary M. Reilly: UCL Queen Square Institute of Neurology
Catherine DeVile: Great Ormond Street Hospital for Children NHS Foundation Trust
Anna Sarkozy: Great Ormond Street Hospital for Children NHS Foundation Trust
Emma Footitt: Great Ormond Street Hospital for Children NHS Foundation Trust
James Davison: Great Ormond Street Hospital for Children NHS Foundation Trust
Shamima Rahman: Great Ormond Street Hospital for Children NHS Foundation Trust
Henry Houlden: UCL Queen Square Institute of Neurology
Enrico Bugiardini: UCL Queen Square Institute of Neurology
Rosaline Quinlivan: UCL Queen Square Institute of Neurology
Michael G. Hanna: UCL Queen Square Institute of Neurology
Jana Vandrovcova: UCL Queen Square Institute of Neurology
Robert D. S. Pitceathly: UCL Queen Square Institute of Neurology

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial ‘no primary findings’ (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk .

Date: 2022
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DOI: 10.1038/s41467-022-32908-7

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