Identification of a unique, de novo MYCBP2 variant in an individual with highly superior autobiographical memory

Highly Superior Autobiographical Memory (HSAM) is an extremely rare condition characterized by an individuals unparallelled ability to recall personal past events with exceptional detail and accuracy, including exact dates and days of the week, spanning many decades1-3. The molecular underpinnings of HSAM are unknown. Here, we investigated an individual with HSAM through neuropsychological testing, structural brain imaging, and genetic analyses. HSAM was confirmed as an isolated exceptional cognitive ability, with brain imaging revealing exceptionally large volumes of regions within the hippocampal formation, which have been previously linked to autobiographical memory. Using whole exome sequencing of the HSAM individual and their unaffected parents, we identified a unique de novo missense variant in MYCBP2, which encodes an E3 ubiquitin-protein ligase4,5. To explore the potential behavioral consequences of this variant, we introduced the homologous variant into C. elegans, which resulted in reduced forgetting and increased membrane-bound glutamate receptor in relevant neuronal cells. These findings show that the studied HSAM individual carries a unique, de novo missense variant in MYCBP2, which reduces forgetting in a model organism. The identification of functionally relevant genetic variants in individuals with superior memory traits has the potential to inform future research into memory-modulating therapies.