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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-03085-5

摘要内容如下：

大多数智障人士（ID）在基因检测后没有接受分子诊断。为了确定ID的新病因，我们进行了遗传关联分析，比较了5，529例无关病例和46，401例无关对照中41，132个非编码基因的罕见变异负担。RNU4-2编码U4 snRNA，是剪接体的关键成分，是最强的相关基因。我们将47例RNU4-2两个区域的新发变异与以ID、小头畸形、身材矮小、肌张力低下、癫痫发作和运动迟缓为特征的综合征的病因联系起来。我们在三个样本中重复了这一发现，使病例数达到73例。国家基因组诊断数据分析显示，RNU4-2是比任何以前报道的常染色体基因更常见的神经发育异常病因基因。我们的发现增加了神经疾病病因中剪接体功能障碍的证据。

英文原文如下：

Abstracts

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 non-coding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 snRNA, a critical component of the spliceosome, was the most strongly associated gene. We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures and motor delay. We replicated this finding in three collections, bringing the number of cases to 73. Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene. Our findings add to growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.

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