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Annual Review of Pathology: Mechanisms of Disease

Volume 20, 2025

Somatic Mosaicism in Brain Disorders

Abstract

Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable finding is that the effect of somatic mosaicism on clinical outcomes can vary depending on contextual factors, such as the developmental origin of a variant or the number and type of cells affected. In this review, we highlight current knowledge regarding the role of somatic mosaicism in brain disorders and how biological context can mediate phenotypes. First, we identify the origins of brain somatic variation throughout the lifespan of an individual. Second, we explore recent discoveries that suggest somatic mosaicism contributes to various brain disorders. Finally, we discuss neuropathological associations of brain mosaicism in different biological contexts and potential clinical utility.

Keyword(s): development, lineage, mosaicism, neurological disorders, neuropathology, somatic variant
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/content/journals/10.1146/annurev-pathmechdis-111523-023528
2025-01-24
2025-06-20
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Somatic Mosaicism in Brain Disorders
Annual Review of Pathology: Mechanisms of Disease 20, 13 (2025); https://doi.org/10.1146/annurev-pathmechdis-111523-023528
/content/journals/10.1146/annurev-pathmechdis-111523-023528
/content/journals/10.1146/annurev-pathmechdis-111523-023528
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