Rare deleterious variants with large effect sizes offer a unique opportunity to understand the pathophysiology of neurodevelopmental disorders and provide insights into mechanism-based therapies.

For the past two decades, we have focused a rare genetic disorder – Tuberous Sclerosis Complex (TSC). We have taken a multi-pronged approach characterizing this disease with cellular and animal models as well as with detailed prospective clinical studies. Our preclinical studies have indicated that TSC1/2 loss of function results in neuronal connectivity and excitability abnormalities due to mTOR hyperactivation. These results have contributed to clinical biomarker identification and treatment trials in TSC. Now, we are extending our findings from TSC to other genetic disorders which impinge on the mTOR pathway by studying their pathobiology in a comparative manner to accelerate the clinical trial readiness across a number of developmental synaptopathies, leveraging several sites around the United States that phenotype patients collaboratively using standard operating procedures.

Identification of rare genetic variants has changed the landscape of research in this field; however, to translate these discoveries into rational, mechanism-based, safe, and effective treatments for neurodevelopmental disorders will require building and sustained support of networks/consortia that work closely with patient communities and industry partners.

Keywords: Autism, tuberous sclerosis, PTEN, Shank3, MRI, EEG, prevention