A collaborative research study co-led by scientists at the Icahn School of Medicine at Mount Sinai and the Liber Institute for Brain Development has for the first time identified a biological process that may help explain how the brain develops differently in people with Down syndrome. The study was a collaboration among scientists from the Icahn School of Medicine at Mount Sinai, the Lieber Institute for Brain Development, the Medical University of Sofia in Bulgaria, and the University of Arizona.
The findings, published March 31 in Nature Communications [https://doi.org/10.1038/s41467-026-70217-5], revolve around a gene that produces an enzyme called ADARB1 (also known as ADAR2), a molecule that helps edit genetic messages inside cells. Too much of this enzyme causes RNA messages to be altered too early and too extensively in developing brain cells of individuals with Down syndrome, thereby affecting how brain cells communicate and how brain circuits form.
Down syndrome, also known as trisomy 21, occurs when an individual has an extra copy of chromosome 21, where the ADARB1 gene is located. While the extra chromosome has long been known to influence development, how it changes early brain formation has remained unclear.
“These findings help us understand how an extra copy of chromosome 21 reshapes the brain from the earliest stages of development,” said author Michael S. Breen, PhD, Associate Professor of Genetics and Genomic Sciences, and Psychiatry, at Mount Sinai. “This is exciting because we are starting to uncover how this genetic imbalance leads to changes in the brain, linking the extra chromosome to increased levels of a key RNA editing enzyme, and subsequent accelerated RNA editing in important neuronal genes. RNA editing is a natural process that is highly active in early development and fine-tunes how proteins function in neurons. We found that RNA editing occurs earlier and more extensively in trisomy 21 and this early shift may influence how brain circuits are formed from the very beginning.”
Studying the Developing Brain
The research team analyzed brain tissue collected between 13 and 22 weeks after conception, an important time for early brain development. These samples, obtained through collaboration with colleagues at the Lieber Institute for Brain Development and the Medical University of Sofia in Bulgaria, included tissues from 20 individuals with trisomy 21 and 27 individuals without the condition. The study focused on two brain regions important for learning and memory: the prefrontal cortex and the hippocampus.
Using advanced RNA sequencing, the team examined gene activity and RNA editing across the entire set of RNA messages in each brain sample. They found widespread disruption of gene expression during mid-gestation in trisomy 21. One of the most consistently over-expressed genes was ADARB1 . The resulting increased levels of the ADARB1 enzyme were associated with higher levels of RNA editing throughout the brain.
The team also observed excessive editing in GRIA2 , GRIA3 , GRIK2 , and GABRA3 , key glutamate and GABA-receptor genes that help regulate how neurons send and receive signals. This editing leads to RNA recoding, a process in which a single nucleotide change alters the amino acid sequence of the resulting protein, directly modifying its function. These premature molecular changes are predicted to alter the balance between excitatory and inhibitory signaling at a time when neural circuits are actively being established.
Confirming the Findings
To strengthen their findings, the researchers performed a combined analysis of nine independent human trisomy 21 datasets. The combined analysis showed the same pattern: higher ADARB1 enzyme levels and increased RNA editing linked to an extra copy of chromosome 21 across multiple independent human datasets.
A New Way to Understand Brain Development in Down Syndrome
The study identifies ADARB1 -driven RNA editing dysregulation as a fundamental molecular consequence of chromosome 21 triplication in Down syndrome.
Their finding that excess ADARB1 enzyme drives premature and excessive RNA recoding during critical windows of fetal brain development directly links gene dosage imbalance to altered neuronal signaling.
“These findings redefine Down syndrome neuropathology to include disrupted post-transcription regulation and establish RNA editing as a measurable biomarker of early brain circuit development and a promising avenue for therapeutic intervention,” said author Joseph D. Buxbaum, PhD, Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences, at Mount Sinai. “This study was only possible because of a truly collaborative effort across multiple institutions all focused on understanding how an extra copy of chromosome 21 affects the developing brain.”
Researchers say the findings open the door to new ways of measuring early brain development and may eventually help guide precision treatments aimed at improving neurological and behavioral outcomes in Down syndrome.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek ’s ® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report 's ® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report ® “Best Hospitals” Honor Roll for 2025-2026.
About the Lieber Institute for Brain Development
The mission of the Lieber Institute for Brain Development and the Maltz Research Laboratories is to translate the understanding of basic genetic and molecular mechanisms of schizophrenia and related developmental brain disorders into clinical advances that change the lives of affected individuals. LIBD is an independent, not-for-profit 501(c)(3) organization and a Maryland tax-exempt medical research institute affiliated with the Johns Hopkins University School of Medicine. The Lieber Institute’s brain repository of nearly 5,000 human brains is the largest collection of postmortem brains for the study of neuropsychiatric disorders worldwide.
For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook , Instagram , LinkedIn , X , and YouTube .
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Nature Communications
Observational study
People
Trisomy 21 Drives ADARB1 Overexpression and Premature RNA Recoding in the Developing Fetal Brain
31-Mar-2026