Somatic mosaicism and neurodevelopmental disease

Traditionally, we have considered genetic mutations that cause neurodevelopmental diseases to be inherited or de novo germline mutations. Recently, we have come to appreciate the importance of de novo somatic mutations, which occur postzygotically and are thus present in only a subset of the cells of an affected individual. The advent of next-generation sequencing and single-cell sequencing technologies has shown that somatic mutations contribute to normal and abnormal human brain development. Somatic mutations are one important cause of neuronal migration and brain overgrowth disorders, as suggested by visible focal lesions. In addition, somatic mutations contribute to neurodevelopmental diseases without visible lesions, including epileptic encephalopathies, intellectual disability, and autism spectrum disorder, and may contribute to a broad range of neuropsychiatric diseases. Studying somatic mutations provides insight into the mechanisms underlying human brain development and neurodevelopmental diseases and has important implications for diagnosis and treatment.