The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

中文翻译：

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RNA外泌体基因EXOSC5中的双等位基因变异与发育迟缓、身材矮小、小脑发育不全和运动无力有关。

RNA外泌体是编码和非编码RNA加工和/或降解所需的必需核糖核酸酶复合物。我们在EXOSC5 中鉴定了五名具有双等位基因变异的患者，其编码 RNA 外泌体的结构亚基。这些患者的临床特征包括发育迟缓、身材矮小、喂养困难、影响运动技能的发育迟缓、肌张力减退和内斜视。脑部MRI显示小脑发育不全和脑室扩大。虽然我们确定了五名患者，但详细研究了三名具有不同EXOSC5变异的患者。第一位患者的缺失涉及EXOSC5 的外显子 5-6和错义变异 p.Thr114Ile，它们是通过反式遗传的，第二名患者是 p.Leu206His 纯合子，第三名患者的 19 号染色体是父本同二体，p.Met148Thr 是纯合子。确定的另外两名患者是在EXOSC5和 p.Thr114Ile 错义变异中具有早期移码突变的兄弟姐妹，这些突变是反式遗传的。我们采用了三种互补的方法来探索大脑发育对EXOSC5的需求，并评估致病性EXOSC5变异的后果。斑马鱼中exosc5的功能丧失导致尾巴/身体缩短和弯曲，眼睛/头部尺寸减小和水肿。我们模拟了致病性EXOSC5出芽酵母和哺乳动物细胞中的变异。这些变异中的一些会导致 RNA 外泌体功能缺陷以及与其他 RNA 外泌体亚基的相互作用发生改变。这些发现扩大了编码与人类疾病相关的 RNA 外泌体亚基的基因数量，同时也表明疾病机制因特定的致病变异而异。