RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi‐allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi‐allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.

中文翻译：

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EXOSC1 中的双等位基因错义变异 p.Ser35Leu 与脑桥小脑发育不全有关

RNA 外泌体是一种高度保守的核糖核酸酶复合物，对 RNA 加工和降解至关重要。据报道，外泌体亚基EXOSC3、EXOSC8和EXOSC9中的双等位基因变异分别导致桥脑小脑发育不全 1B 型、1C 型和 1D 型，而EXOSC2中的双等位基因变异导致身材矮小、听力损失、色素性视网膜炎和独特的面容。我们确定了一名 8 个月大的男性，患有发育迟缓、小头畸形、轻微畸形和肌张力减退。神经影像学发现脑桥小脑发育不全和髓鞘形成延迟。一个同样受累的哥哥姐姐在 4 岁 6 个月大时死亡。染色体微阵列返回正常结果。外显子组测序显示纯合错义变异，c.104C > T p.(Ser35Leu) inEXOSC1 (NM_016046.5) 作为可能的候选者。计算机诱变显示与邻近的 Leu37 残基失去极性接触。定量实时 PCR 表明EXOSC1转录水平没有明显差异。免疫印迹和蓝色原生 PAGE 分别显示先证者中 EXOSC1 蛋白水平和 EXO9 复合物的减少。我们在此报告了一个在EXOSC1中具有双等位基因变异体 c.104C>T p.(Ser35Leu)和 1 型脑桥小脑发育不全的临床特征的个体。免疫印迹和蓝色天然 PAGE 为该变异体的致病性提供了证据。因此，我们建议EXOSC1作为脑桥小脑发育不全的新候选基因。