Evaluate the functional consequences of CIC missense variants seen in individuals with neuropsychiatric disease.

Our lab discovered heterozygous de-novo truncating variants in the transcriptional repressor CIC lead to CIC Haploinsufficiency Syndrome (CHS), a neurodevelopmental disorder characterized by intellectual disability, ADHD, autism, and seizures. To understand how loss of CIC leads to these phenotypes, we generated both germline and conditional loss-of-function (LOF) mouse models. Cic^null/null mice die perinatally, however, conditional LOF models ablating Cic in different brain regions recapitulate CHS phenotypes, suggesting that mice are an ideal system to study CIC biology. We recently identified individuals with CHS phenotypes and denovo CIC missense variants of unknown significance.  Additionally, rare de-novo CIC missense variants have been described in schizophrenia cohorts. We propose these missense variants alter CIC function along a spectrum, with more severe variants leading to CHS and milder variants leading to schizophrenia.

We used CRISPR-Cas9 to generate six knock-in (KI) mouse models, each harboring a patient variant of unknown significance from individuals with either CHS (4) or schizophrenia (2). Next, we characterized the allelic series examining viability, behavior, and downstream gene expression.

We generated homozygous mice for each variant and examined viability. Interestingly, three lines (2 CHS and 1 schizophrenia) resulted in lethality by postnatal-day 21. Conversely, the three lines that did not alter viability showed no behavioral deficits after a complete behavior battery, suggesting they may not be pathogenic. Transcriptomic analysis of forebrain from each line compared to Cic^+/+ and Cic^null/null directly correlates with survival data and allows us to quantitatively assess the severity of each variant. We are investigating if unique transcriptomic signatures exist between CHS and schizophrenia variants.

In-vivo mouse studies allowed us to confirm pathogenicity of CIC missense variants and establishing that CIC variants cause a phenotypic spectrum, ranging from childhood neurodevelopmental phenotypes to adult-onset schizophrenia.