Rare Homozygous Variants in INSR and NFXL1 Are Associated with Severe Treatment-Resistant Psychosis

Psychosis constitutes a cardinal component of schizophrenia and affects nearly fifty percent of those with bipolar disorder. We sought to molecularly characterize psychosis segregating in consanguineous families. Participants from eight multiplex families were evaluated using standardized testing tools. DNA was subjected to exome sequencing followed by Sanger sequencing. Effects of variants were modeled using in-silico tools, while cDNA from a patient's blood sample was analyzed to evaluate the effect of a splice-site variant. Twelve patients in six families were diagnosed with schizophrenia, whereas four patients from two families had psychotic bipolar disorder. Two homozygous rare deleterious variants in <i>INSR</i> (c.2232-7T>G) and <i>NFXL1</i> (c.1322G>A; p.Cys441Tyr) were identified, which segregated with severe treatment-resistant psychosis/schizophrenia in two families. There were none, or ambiguous findings in the other six families. The predicted deleterious missense variant affected a conserved amino acid, while the intronic variant was predicted to affect splicing. However, cDNA analysis from a patient's blood sample did not reveal an aberrant transcript. Our results indicate that <i>INSR</i> and <i>NFXL1</i> variants may have a role in psychosis that requires to be investigated further. Lack of molecular diagnosis in some patients suggests the need for genome sequencing to pinpoint the genetic causes.