近日，荷兰伊拉斯谟大学教授Ernest Turro及其课题组探明了RNU2-2的双等位基因变异导致最普遍的隐性神经发育障碍。该研究于2026年3月30日发表于国际一流学术期刊《自然—遗传学》杂志上。

研究组最近发现，snRNA基因RNU4-2和RNU2-2的突变是显性神经发育障碍（NDDs）的普遍主题。通过遗传关联，研究人员证明了RNU2-2综合征存在隐性形式。该课题组人员推断一个对数贝叶斯因子的关联的隐性模型为18.2。在该模型的条件下，17个罕见变异的后验致病性概率为0.8。这个保守阈值确定了18个先证和5个受影响的兄弟姐妹，每个人在这些变体中携带两个反式等位基因。放宽阈值>0.6确定了另外13个候选先证者。

该研究团队确定了复制集合中的另外九种情况。受影响的个体有智力残疾、全面发育迟缓和癫痫发作。隐性RNU2-2综合征占目前通过测序诊断的隐性NDD家庭的约10%，影响的家庭数量约为显性RNU4-2相关NDD ReNU综合征的60%。预计这些变异会破坏茎环和U2-2 snRNA的结合域。全血RNA测序数据显示，在双等位基因病例和单等位基因携带者中，致病性U2-2等位基因的表达减少了90%，尽管在携带者中存在野生型补偿，这表明表达缺失机制。

附：英文原文

Title: Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder

Author: Greene, Daniel, Mendez, Rodrigo, Lees, Jon, Barbosa, Mafalda, Bruselles, Alessandro, Chiriatti, Luigi, Ferraro, Federico, Mancini, Cecilia, Schot, Rachel, Sleutels, Frank, Bertini, Enrico, Bonner, Devon E., Bouman, Arjan, Brooks, Alice S., Cassini, Thomas A., Ezell, Kimberly M., Gomez-Ospina, Natalia, Kleefstra, Tjitske, ODonoghue, Michael, Rives, Lynette, Shashi, Vandana, Spillmann, Rebecca C., Wafik, Mohamed, Freson, Kathleen, Barakat, Tahsin Stefan, Tartaglia, Marco, Bernstein, Jonathan A., Mumford, Andrew D., Wheeler, Matthew T., Turro, Ernest

Issue&Volume: 2026-03-30

Abstract: We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.

DOI: 10.1038/s41588-026-02539-5

Source: https://www.nature.com/articles/s41588-026-02539-5