Somatic Mutation in Pediatric Neurological Diseases

Abstract

Genetic variation contributes significantly to brain function and dysfunction, and studying the genetic factors responsible for neurological phenotypes is tremendously valuable for understanding brain development, physiology, and pathophysiology, as well as for advancements in disease diagnostics and therapeutics. Many genetic determinants of neurobiology are inherited from parents through the germline and are present in all cells of an individual, but others, known as somatic or mosaic mutations, may be acquired post-conception and are therefore present in only a subset of an individual’s cells. While the relationship between somatic mutation and cancer is clear, recent studies have also established a role for somatic mutations in several non-malignant neurological diseases of childhood, including cerebral cortical malformations and epilepsy disorders, autism spectrum disorder, and other neuropsychiatric diseases.

Keywords: Autism spectrum disorder; Cortical malformation; Development; Mosaic fraction; Mosaicism; Somatic mutation.

Figure 1

Developmental timing of somatic mutation acquisition determines distribution in the adult body. A somatic mutation that occurs in a developing embryo prior to gastrulation (far left, magenta) will have a broad distribution throughout the adult body and will be present in tissues derived from all three developmental germ layers. A somatic mutation that occurs during neurulation (center left, yellow) will be present throughout the central nervous system of the adult but absent in non-neural tissues. This mutation will only be detectable through studying CNS-derived DNA. Somatic mutations that occur early during cortical neurogenesis may be present in large regions of the adult brain (center, green), and may cause disease phenotypes, such as in hemimegalencephaly. The later a mutation occurs within cortical development, the more restricted its distribution will be in the adult brain. Mutations occurring during the middle of cortical neurogenesis may have varied distributions throughout portions of the cortex (center right, blue), and mutations occurring late in cortical development may have very restricted distributions within very small regions of cortex (right, purple), as in focal cortical dysplasias. These mutations will only be detected by studying DNA derived from the affected brain region.