We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

我们先前已经描述了由SMG9中纯合功能丧失变异引起的心，眼和脑畸形综合征，该变异编码无意义介导的衰变（NMD）机制的关键组成部分。在这里，我们描述了四个近亲家族，它们在SMG8中具有四个不同的可能有害的纯合变异体，编码SMG9的结合伴侣。观察到的表型非常类似于与SMG9相关的表型包括严重的整体发育迟缓，小头畸形，面部畸形和先天性心脏和眼睛畸形。RNA-seq分析显示，mRNA表达水平普遍升高，核心NMD底物明显过量表达。我们还发现UMD1的磷酸化增加，这是NMD中一个关键的SMG1依赖性步骤，最有可能代表SMG8介导的SMG1激酶活性抑制作用的丧失。我们的数据表明，SMG8和SMG9缺乏症导致重叠的发育障碍，最有可能通过机械方式收敛于受损的NMD。