The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of
neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in
GABA receptor genes being involved in neurologic diseases, particularly the
epilepsies. In addition, a substantial number of variants and mutations have been found in
GABA receptor genes in patients with
autism,
schizophrenia, and addiction, suggesting potential links between the
GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in
glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A
N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which
seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for
epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor mutations, most of which occur within GRIA3, are from patients with
intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for
kainate receptor variants is
intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic
GABA and
glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.