Partial Pharmacological “rescue” and MRS Spectroscopy in Two Carriers of a Rare Marker Chromosome Containing Extra Copies of the GLDC Gene Encoding a Glycine-Degrading Enzyme Implicate NMDA Receptor Hypofunction in Psychosis

The increased burden of rare copy number variants (CNVs) in neuropsychiatric disorders is well established but linking mutations in specific genes to underlying disease biology and targeted treatment is challenging. Here we describe 1) the molecular genetic architecture of a complex genomic rearrangement that includes the glycine decarboxylase (GLDC) gene, implicating NMDAR-receptor hypofunction in two individuals with different psychotic disorders, 2) the results of placebo-controlled augmentation trials that targeted the reduced glycine and D-serine levels predicted to result from the GLDC mutation, and 3) efforts to characterize the effect of this mutation on glycine metabolism in the brain using magnetic resonance spectroscopy (MRS).