July 2026

NEUROSCIENCES

STUDY IDENTIFIES NEW GENETIC VARIANTS THAT CAUSE RARE TUMOR DISORDER

A recent Northwestern Medicine study offers new data showing previously unknown genetic variants that cause the development of tuberous sclerosis complex, according to findings published in Nature Communications.

In Pursuit of More Precision
Tuberous sclerosis complex (TSC) is caused by genetic variants in two mTOR pathway genes: TSC1 and TSC2. When one of them doesn’t work normally, mTOR pathway activity is elevated, leading to pathology.   

Current functional assays, however, haven’t been able to determine the significance of thousands of already observed TSC2 missense variants. Missense variants cause a single amino acid among over 1,800 to be substituted for a different amino acid.  

“Missense variants in TSC2 are often classified as variants of uncertain significance, which act as barriers to a precise genetic diagnosis of TSC. A precise genetic diagnosis can be valuable to enable access to precision treatment with mTOR pathway inhibitors,” explains Jeffrey Calhoun, PhD, senior author. 

Addressing Ambiguity
Dr. Calhoun’s team used next-gen sequencing to measure the steady-state abundance, or the stable level of proteins created, of nearly 9,000 TSC2 missense variants.  

Next, the scientists developed an mTOR pathway activity assay using genome editing and cell sorting based on an mTOR pathway biomarker to create activity scores for 391 missense variants.  

“Say we have 10,000 cells. Each of those cells has a different missense variant, and then we can sort those cells based on how active the mTOR pathway is. If it is highly active, those cells are likely to harbor a pathogenic variant that causes TSC. If instead the cell exhibits normal levels of mTOR activity, those genetic variants are likely to be benign,” says Dr. Calhoun.  

Of the total missense variants assayed, the scientists found that 14% had altered TSC2 abundance and nearly 18% had altered mTOR pathway activity.  

Overall, the data reclassified 78.8% of TSC2 missense variants of uncertain significance.
  
A More Definitive Path to Diagnosis
The new data could help improve genetic diagnosis of TSC and support proper surveillance, family planning and precision treatment. The data may also enable patients to enroll in gene replacement clinical trials, during which individuals receive healthy copies of either TSC1 or TSC2.  Dr. Calhoun’s team now aims to scale all missense variants in the TSC2 gene and eventually the TSC1 gene.  

“Our amazing collaborators at the University of Washington, Dr. Doug Fowler and Dr. Rich James, and the talented scientists in their laboratories made significant contributions to this work. Their work, and ours, will have a lasting contribution to the TSC community,” Dr. Calhoun adds. 

Carina Biar, a former Northwestern University undergraduate student, was a co-first author of the study. Gemma Carvill, PhD, was a co-author.  

This work was supported by an American Epilepsy Society Junior Investigator Award and a TSC Alliance Research Grant, the National Institutes of Health National Human Genome Research Institute IGVF Program (HG011969), and in part by National Human Genome Research Institute Interdisciplinary Training in Genome Sciences Grant T32HG000035. 
Jeffrey Calhoun, PhD, Research Assistant Professor in the Ken and Ruth Davee Department of Neurology’s Division of Epilepsy and Clinical Neurophysiology, was senior author of the study. 

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