Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

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 input improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial diseases (NPD) reports. NPD 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 maritime 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.

William L Macken, Micol Falabella, Caroline McKittrick, Chiara Pizzamiglio, Rebecca Ellmers, Kelly Eggleton, Cathy E Woodward, Yogen Patel, Robyn Labrum, Genomics England Research Consortium, Rahul Phadke, Mary M Reilly, Catherine DeVille, Anna Sarkozy, Emma Foti, James Davidson, Shalima Rahman, Henry Houlden, Enrico Buglidarini, Rosalinde Quinlivan, Michael G Hanna, Jana Vandrováčová, Robert D S Pitceathly