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. This study shows that specialist multidisciplinary input improves diagnostic rates and alters management. WGS was undertaken in 102 adults with diagnostically challenging primary mitochondrial diseases (PMD). A genomic medicine team reviewed NPD cases, enabling bespoke informatic approaches, coordinated phenotypic validation, and functional work. The diagnostic rate increased 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 provides a standardized model of care enhancing diagnostic equity for complex disorders.

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