Rapid exome sequencing for children with severe acute encephalopathy – A case series

Increasingly, next-generation sequencing (NGS) is becoming an invaluable tool in the diagnosis of unexplained acute neurological disorders, such as acute encephalopathy/encephalitis. Here, we describe a brief series of pediatric patients who presented at the pediatric intensive care unit with severe acute encephalopathy, initially suspected as infectious or inflammatory but subsequently diagnosed with a monogenic disorder.

Rapid exome sequencing was performed during the initial hospitalization of three unrelated patients, and results were delivered within 7–21 days. All patients were previously healthy, 1.5–3 years old, of Muslim Arab descent, with consanguineous parents. One patient presenting with acute necrotizing encephalopathy (ANEC). Her sister presented with ANEC one year prior.

Exome sequencing was diagnostic in all three patients. All were homozygous for pathogenic and likely-pathogenic variants associated with recessive disorders; MOCS2, NDUFS8 and DBR1. Surprisingly, the initial workup was not suggestive of the final diagnosis.

This case series demonstrates that the use of rapid exome sequencing is shifting the paradigm of diagnostics even in critical care situations and should be considered early on in children with acute encephalopathy. A timely diagnosis can direct initial treatment as well as inform decisions regarding long-term care.