The basic-Helix-Loop-Helix PER-ARNT-SIM (bHLH-PAS) transcription factors Neuronal PAS 3 and 4 (NPAS3/4) are expressed in several structures of the mammalian brain. To influence transcription, NPAS3 and NPAS4 must heterodimerise with their partner protein Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT). NPAS3 is important for neuronal proliferation during development and in the dentate gyrus of the adult hippocampus. In contrast, NPAS4 is expressed primarily in the adult brain where it maintains neural circuit homeostasis via synaptic modulation. Despite these differences, studies using mouse models have implicated both NPAS3 and NPAS4 in schizophrenia and intellectual disability. However, there is currently a significant gap in the literature concerning mutations in the human NPAS3/4 genes in association with mental illness. There have only been two mutations identified for the human NPAS3 gene, whilst no mutations have been identified for NPAS4. Recently, we have utilised unpublished exome sequencing data to identify individuals with mental illness that have either non-synonymous or truncating mutations for NPAS3/4. It is necessary to identify mutants with deficient transcriptional activity to determine if they are contributing to the disease phenotype. To identify deficient mutants, luciferase reporter gene assays were utilised and only the truncating mutations of NPAS3 and NPAS4 had decreased transcriptional activity. To then investigate a possible mechanism for the reduced reporter activity, we determined the ability of the NPAS3/4 proteins to heterodimerise with their obligate partner ARNT via co-immunoprecipitation. We plan on performing additional mechanistic experiments assessing protein localisation, protein turnover and DNA binding.