Mayo Clinic Uses Genomics to Understand Neurodevelopmental Disorders

Researchers at Mayo Clinic have found genetic variants in SPTBN1, a neuro-associated gene, are the reason behind neurodevelopmental disorders. This application of genomics is the first step in discovering possible therapeutic strategies to treat disorders. Additionally, it increases the number of known genes associated with conditions that impact brain function.

"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," Margot Cousin, PhD, a translational genomics researcher in Mayo Clinic's Center for Individualized Medicine and the study's lead author, said in a press release.

Researchers studied disease causing variants of the SPTB1 in 29 individuals with clinical neurodevelopmental symptoms. These symptoms included language and motor delays, intellectual disabilities, autistic features, seizures, behavioral and movement abnormalities, and variable dysmorphic facial features. The team was able to identify 28 unique variants.

According to Cousin, most of the genetic variants were not inherited. They had recently occurred in those who were infected.

"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," Cousin continued.

"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,” Cousin said.

The SPTBN1 gene codes a protein called beta-two spectrin, which is expressed in the brain and other parts of the body. Beta-two spectrin creates protein networks within the cell, and it is crucial for brain 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. But these differences in functional effects helped to explain the clinical variability we were observing in the patients," Cousin said.

Due to many neurodevelopmental diseases going undiagnosed, the study also highlights the challenges in rare disease genomics. However, Cousin sees change coming for those going undiagnosed.

"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," Cousin said.

"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,” Cousin continued.

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

Cousin explained that continuing research on these genetic findings required persistence.

"The clinical variability we observed in people early on was not very compelling that this could be a single genetic condition," Cousin continued.

"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.”

According to Cousin, the cell-based and animal models created in the study will continue to be an important tool in the advancement of disease mechanisms and discovering 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."