Genetic Analysis of Patients Who Experienced Awareness With Recall While Under General Anesthesia

Jamie W. Sleigh, M.D.; Kate Leslie, M.D.; Andrew J. Davidson, M.D.; David J. Amor, Ph.D.; Peter Diakumis, M.Bioinf.; Vesna Lukic, M.Sci.; Paul J. Lockhart, Ph.D.; Melanie Bahlo, Ph.D.


Anesthesiology. 2019;131(5):974-982. 

In This Article

Abstract and Introduction


Background: Intraoperative 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.

Methods: The 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.

Results: The 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.

Conclusions: Within 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.


Explicit recall of intraoperative events is a rare, but often distressing, phenomenon. We will use the nomenclature awareness with recall for these episodes. For 90% of the population, the amnesic effects of general anesthetic drugs occur at concentrations well below those required for unconsciousness (typically 0.1 to 0.3 minimum alveolar concentration [MAC]).[1] However, in approximately 10 to 25% of awareness with recall patients anesthesia dosing is apparently adequate (greater than 0.5 MAC),[2,3] indicating that the anesthetic drug has failed to disrupt conscious perception and the memory consolidation process. A genetic predisposition for awareness with recall may exist and could explain resistance to levels of anesthesia that are normally considered adequate for the majority of patients. However, we are not aware of any study that has previously investigated this hypothesis.

Many neurobiologic events must be fulfilled to lay down a properly consolidated memory.[4–6] It is noteworthy that the awareness with recall phenotype only reveals itself when patients are exposed to anesthesia; typically, awareness with recall patients display no other identified phenotypic disturbance in day-to-day life, and awareness with recall has no clear demographic or disease associations. Also, the incidence of awareness with recall is low (less than 0.2%).[7] If there is a genetic component to awareness with recall, these observations would suggest one of two parsimonious hypotheses for potential genetic causes of awareness with recall: (1) awareness with recall could be a polygenic trait with common variants in many weakly penetrant genes—and having interactions with other genes or the environment—each contributing a small amount to the risk; or that (2) awareness with recall could be caused by a few rare variants, each with a high penetrance. Identifying common variants of low impact is difficult, and typically involves undertaking a genome-wide association study, usually requiring hundreds if not thousands of affected individuals. Without access to these resources, we undertook a preliminary study examining whether there is evidence for the rare-variant model. To do this we conducted whole exome sequencing of a set of carefully chosen patients who have experienced awareness with recall in the presence of apparently adequate anesthesia concentrations. The identified variants were filtered and prioritized to identify a candidate list of variants/genes that might form a reasonable basis for further investigation of the causes of awareness with recall.