Tuberous sclerosis genetic variants identified in TSC2 study
Northwestern Medicine researchers reported TSC2 variant data that may sharpen diagnosis and guide access to mTOR-targeted treatment.
By Priya Raghavan · Science Reporter
3 min read
A Northwestern Medicine study has identified tuberous sclerosis genetic variants in the TSC2 gene that researchers say can cause the rare tumor disorder. The findings matter because many patients carry DNA changes that genetic testing has not been able to classify clearly, leaving clinicians without firm proof of the diagnosis.
The study, led by Jeffrey Calhoun, Ph.D., a research assistant professor in Northwestern University’s Ken and Ruth Davee Department of Neurology, was published in Nature Communications. Northwestern said the work provides new data on previously unknown variants tied to tuberous sclerosis complex, or TSC.
What is tuberous sclerosis complex?
Tuberous sclerosis complex is a rare genetic disorder that causes benign tumors to form in multiple parts of the body, according to Northwestern. The tumors are most often seen in the skin, brain, eyes, kidneys, heart and lungs.
Northwestern said symptoms differ widely from patient to patient and may include skin changes, seizures, behavioral problems, and heart or lung complications. Clinicians commonly use genetic testing, an electroencephalogram, brain MRI and a physical exam to diagnose the condition.
There is no cure for TSC, Northwestern said, but targeted care can address specific symptoms. Calhoun said a precise genetic diagnosis can also help patients gain access to treatments that inhibit the mTOR pathway.
How do TSC2 variants affect diagnosis?
TSC is caused by variants in two mTOR pathway genes, TSC1 and TSC2, according to the researchers. When either gene does not work normally, activity in the mTOR pathway rises and can contribute to disease.
The diagnostic problem has centered on TSC2 missense variants. Northwestern said these are DNA changes that alter a single amino acid in the TSC2 protein, which contains more than 1,800 amino acids.
Calhoun said many TSC2 missense variants are reported as variants of uncertain significance. That classification can stand between a patient and a clear genetic diagnosis, according to Northwestern.
To test the variants, Calhoun’s team used next-generation sequencing to measure the stable levels of proteins produced by nearly 9,000 TSC2 missense variants. The researchers then built an assay for mTOR pathway activity using genome editing and cell sorting based on a pathway biomarker.
That second step produced activity scores for 391 missense variants, according to Northwestern. Calhoun described the method as a way to sort cells by how active the mTOR pathway is, with high activity pointing toward variants more likely to be disease-causing and normal activity pointing toward variants more likely to be benign.
What did the study find?
Among the missense variants tested, the researchers reported that 14% changed TSC2 abundance and nearly 18% changed mTOR pathway activity. Overall, the study reclassified 212 of 276 TSC2 missense variants that had previously been considered uncertain, or 78.8%.
Northwestern said the results could improve TSC genetic diagnosis and patient care by supporting surveillance decisions, family planning and access to precision therapies. Calhoun also said the data may help patients qualify for gene replacement clinical trials, in which participants receive healthy copies of TSC1 or TSC2.
Calhoun said his group plans to expand the work to all missense variants in TSC2 and later to TSC1. Northwestern also credited collaborators at the University of Washington, including Doug Fowler and Rich James, for contributions to the research.
This story draws on original reporting from Medical Xpress.