• Jamie W Sleigh, Kate Leslie, Andrew J Davidson, David J Amor, Peter Diakumis, Vesna Lukic, Paul J Lockhart, and Melanie Bahlo.
• From Department of Anaesthesiology, Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand (J.W.S.) Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia (K.L.) Centre for Integrated Critical Care (K.L.) Department of Pharmacology and Therapeutics (K.L.) Department of Paediatrics (A.J.D., D.J.A., P.J.L.) Department of Medical Biology (M.B.), The University of Melbourne, Melbourne, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (K.L.) Department of Anaesthesia, Royal Children's Hospital, Melbourne, Australia (A.J.D.) Murdoch Children's Research Institute, Melbourne, Australia (A.J.D., D.J.A.) Royal Children's Hospital, Melbourne, Australia (D.J.A.) Population Health and Immunity Division (P.D., M.B.) Bioinformatics Division (V.L.), The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Australia (P.J.L.).
• Anesthesiology. 2019 Nov 1; 131 (5): 974-982.

BackgroundIntraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations.MethodsThe authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory.ResultsThe authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors.ConclusionsWithin the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.

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