Newly discovered genetic variants in a single gene cause neurodevelopmental disorder

"The gene can now be included in genetic testing for people suspected of having a neurodevelopmental disorder, which may end the diagnostic odyssey these people and their families have endured," says Margot Cousin, Ph.D., a translational genomics researcher in Mayo Clinic's Center for Individualized Medicine and the study's lead author.

For the global study, a collaboration with The University of North Carolina at Chapel Hill, researchers investigated disease-causing variants of the SPTBN1 gene in 29 people with clinical neurodevelopmental symptoms, including language and motor delays, intellectual disability, autistic features, seizures, behavioral and movement abnormalities, and variable dysmorphic facial features. Overall, the team identified 28 unique variants.

Dr. Cousin says most of the genetic variants were not inherited, but rather newly occurred in the patients who were affected.

"We showed through multiple different model systems, including computational protein modeling, human- and mouse cell-based systems, patient-derived cell systems, and in vivo mouse studies, the impact the variants have on the function of the protein encoded by the SPTBN1 gene," Dr. Cousin explains. "I had a hunch this gene was the answer for these patients, but it wasn't until we accrued and studied more patients with variants in SPTBN1 that we could see how the variants had damaging effects on the protein and we could begin putting the story together."

The SPTBN1 gene codes for a protein called beta-two spectrin, which is abundantly expressed in the brain and other parts of the body. Beta-two spectrin makes protein networks within cells, and it is essential for the brain's development and connectivity.

"Interestingly, some of the variants behave very differently than the others, where some make the beta-two spectrin protein unstable and some disrupt its ability to make important interactions with other proteins," Dr. Cousin says. "But these differences in functional effects helped to explain the clinical variability we were observing in the patients."

The study also demonstrates the challenges in rare disease genomics, as many neurodevelopmental diseases remain undiagnosed under the standard of care.

But Dr. Cousin is hopeful the tide is turning.

"Advances in genome sequencing and our ability to interpret the enormous amount of data we generate with various types of 'omic' technologies has led to increases in the discovery of novel disease-causing genes," Dr. Cousin says. "But rigorous studies encompassing the clinical manifestations of affected people and the underlying mechanism of disease are often critical to solidifying a new gene-disease relationship."

Omic technologies include the detection of genes, genomics; messenger RNA, transcriptomics; proteins, proteomics; and metabolites, metabolomics.

Dr. Cousin emphasizes that bringing this genetic finding to light required much perseverance.

"The clinical variability we observed in people early on was not very compelling that this could be a single genetic condition," she explains. "The gene, however, had many of the hallmarks of a rare monogenic disease gene, including that the normal population doesn't have variation in SPTBN1, other spectrin genes cause neurological syndromes, and mouse studies completely lacking the protein have severe defects."

Dr. Cousin says the cell-based and animal models developed in the study will continue to be invaluable in advancing knowledge of the disease mechanisms and testing any potential therapeutic strategies.

"While there is not yet a specific treatment available for people affected by SPTBN1-associated disease, we can now provide patients with an answer to the root cause of disease, which is the most important first step toward finding a cure."