Unlocking the Mind: The Intersection of Genetics and Neurology

At The Intersection of genetics and neurology, researchers at the Icahn School of Medicine at Mount Sinai, alongside colleagues from the University of Bristol, KU Leuven, and NIHR Bioresource, have discovered a neurodevelopmental condition affecting tens of thousands globally, caused by mutations in a single gene. The researchers published the study in the May 31 online issue of Nature Medicine.

The results will help individuals with neurodevelopmental problems receive better clinical diagnostic care.

Through thorough genomic investigation, researchers found mutations in the tiny non-coding gene RNU4-2 cause previously unexplained developmental symptoms. Non-coding genes are DNA segments that don’t result in protein synthesis. The researchers compared the burden of uncommon genetic variants in 41,132 non-coding genes between 5,529 unrelated individuals with intellectual disability and 46,401 unrelated controls using whole-genome sequencing data from the National Genomic Research Library in the United Kingdom.

*The Intersection* of genetics and neurology shows this finding ranks second to Rett syndrome in prevalent single-gene origins. Interestingly, these mutations are usually spontaneous rather than hereditary, shedding light on the origins of the illness.

The Intersection of Genetics and Neurology: Uncovering Rare Non-Coding Gene Variants Behind Neurodevelopmental Disorders

According to Daniel Greene, PhD, assistant professor of genetics and genomic sciences at Icahn Mount Sinai and visiting scholar at the University of Cambridge, “we performed a large genetic association analysis to identify rare variants in non-coding genes that might be responsible for neurodevelopmental disorders.” Greene, the study’s first author, noted, “In The Intersection of genetics and neurology, it is rare to uncover a single gene with variations causing tens of thousands of patients to suffer from a rare disease. For years, our discovery escaped experts due to sequencing and analytical difficulties.”

More than 99 percent of genes known to carry mutations causing neurodevelopmental diseases encode proteins. The scientists postulated that mutations causing intellectual disability might also occur in non-coding genes, which don’t make proteins. Neurodevelopmental disorders, often apparent before school age, impact personal, social, academic, or occupational functioning due to developmental deficiencies. Particularly, intellectual disability refers to marked impairments in adaptive behaviour and intellectual functioning (such as learning, reasoning, and problem-solving).

Revolutionizing Diagnosis: Uncovering Key Genetic Changes and Exploring Molecular Pathways for Targeted Therapies

Ernest Turro, PhD, an associate professor of genetics and genomic sciences at Icahn Mount Sinai and a visiting scholar at the University of Cambridge, is the senior study author. “The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants, and fungi,” he says. “After genetic testing, the majority of individuals with neurodevelopmental disorders do not obtain a molecular diagnosis. Thanks to this study, tens of thousands of families can now end diagnostic journeys with a molecular diagnosis.

Scientists plan to explore The Intersection of molecular pathways causing the disease; therefore, they aim to offer insights for targeted therapies.

Revealing Hidden Causes: Non-Coding Gene Mutations in Common Neurodevelopmental Disorders

Heather Mefford, MD, PhD, from St. Jude Children’s Research Hospital, did not conduct this research on neurological diseases. She finds it remarkable that focusing on coding genes caused them to miss a common neurodevelopmental disorder cause. Identifying mutations in non-coding genes, especially RNU4-2, reveals an important but previously unrecognized cause of disorders. It highlights the need to explore non-coding regions, potentially revealing more genetic causes and opening new research avenues.

The article is entitled “Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders.”

Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol), Jarvis, MD (Birmingham Women’s Hospital), Thys, and Freson, PhD (KU Leuven), co-authored the paper.
A portion of the work was funded by NIH grants R01HL161365 and R03HD111492