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Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN Binding Protein 2 (RANBP2) associated Acute Necrotizing Encephalopathy sub-type 1 (ANE1). We provide clinical, genetic and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.
Evaluation of clinical data, neuroradiological studies, genomic sequencing and protein immunoblotting results in eight children from four families who experienced acute febrile encephalopathy.
All eight healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death, to severe neurological deficits, to normal outcomes. The neuroradiological findings overlapped with ANE, but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1; a subset studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in one family.
Biallelic variants in RNH1 confer susceptibility to a sub-type of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies such as RNH1 and improve outcomes in the probands and at-risk siblings.
Accepted: May 10, 2023
Received in revised form: May 9, 2023
Received: March 13, 2023
Publication stageIn Press Accepted Manuscript
Conflict of interest:
Rebecca Ganetzky is a paid consultant for Minovia Therapeutics and NurtureGenomics.
Neal Sondheimer is employed by Synlogic, Inc.
None for the other authors.
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.