Mount Sinai Team Identifies Recessive ReNU2 Syndrome as the Most Prevalent Recessive Neurodevelopmental Disorder Ever Found
Biallelic RNU2-2 variants cause a newly characterized neurodevelopmental disorder that researchers estimate accounts for roughly 10 percent of recessive NDD cases with a known genetic cause.
Overview
A team led by researchers at the Icahn School of Medicine at Mount Sinai has described a previously uncharacterized recessive neurodevelopmental disorder that they estimate is the most prevalent recessive condition of its kind ever identified. The paper, titled “Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder,” was published in Nature Genetics on 30 March 2026.
The condition, now called recessive ReNU2 syndrome, is caused by inheriting two altered copies of RNU2-2, a short non-coding gene that encodes a working component of the spliceosome. It accounts for roughly 10 percent of recessive NDD cases with a known genetic cause, according to Mount Sinai’s release distributed via EurekAlert.
What We Know
The study was led by first author Daniel Greene and senior author Ernest Turro of the Icahn School of Medicine at Mount Sinai, with collaborators at Stanford University, the University of Bristol and other institutions in the UK, the Netherlands, Belgium and Italy, the University of Bristol said.
The team analysed whole-genome sequencing records from 14,805 individuals with a neurodevelopmental disorder and 52,861 controls, scanning rare variants across more than 41,000 non-coding genes, according to the EurekAlert release. The cohort was drawn largely from the UK’s National Genomics Research Library, which includes data from the 100,000 Genomes Project and the NHS Genomic Medicine Service.
The pathogenic variants identified are biallelic, meaning affected children inherit one altered copy from each typically unaffected parent. The combined effect is a near-complete absence of the U2-2 small nuclear RNA molecule that RNU2-2 normally produces, as described in the Nature Genetics paper. Because U2 snRNA is part of the major spliceosome, its loss disrupts processing of messenger RNAs across the genome, with particularly visible consequences for brain development.
Clinical features reported in the cohort include low muscle tone, developmental delays and limited speech, with some children also showing learning difficulties, autism traits, epilepsy, movement disorders, difficulty walking, and in severe cases feeding or respiratory problems, Mount Sinai described via EurekAlert.
The investigators estimate the recessive form is roughly 60 percent as common as the previously described dominant ReNU syndrome (caused by variants in the related RNU4-2 gene), an unusual distribution because dominant disorders typically outnumber recessive ones among the most common monogenic NDDs, the EurekAlert release noted. Andrew Mumford, Emeritus Professor of Genomic Medicine at the University of Bristol and a co-author, said the paper “completes a set of three landmark genetic discoveries from our team that have identified faults in two hitherto unsuspected genes as a common cause of what can sometimes be a devastating developmental disorder,” according to the University of Bristol.
“Our discovery gives families something they’ve often waited years for — a clear molecular explanation for their child’s condition,” Greene said in the EurekAlert release.
The Nature Genetics paper also argues that, because the phenotype is driven by loss of U2-2 RNA, reintroducing even small amounts of wild-type U2-2 RNA into neurons could in principle be therapeutic, pointing to gene replacement as a plausible future avenue, the authors write.
This finding builds on the team’s earlier work on the dominant form of RNU2-2 disease, in which de novo single-nucleotide changes in the gene were shown to cause a severe neurodevelopmental disorder with prominent epilepsy.
What We Don’t Know
The Nature Genetics paper does not establish a causal mechanism at cellular resolution: exactly which splicing events are most disrupted in patient neurons, and how disruption translates to the observed range of symptoms, remains to be worked out, the authors note.
No approved treatment exists. Gene replacement is described as a plausible strategy but has not been demonstrated in animal models of recessive ReNU2 syndrome in the paper, according to the Nature Genetics report. Mount Sinai is enrolling families into a natural-history study called INDEED to collect biospecimens and clinical data that could support future trials, the EurekAlert release said.
The prevalence estimate — approximately 10 percent of recessive NDD cases with a known genetic cause — is derived from cohorts concentrated in the UK and other high-income countries. How the estimate generalises globally, particularly in populations with different patterns of consanguinity and ancestry, is an open question the authors flag for further study, the EurekAlert release said.