Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.
Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
J Hum Genet. 2021 Apr;66(4):401-407. doi: 10.1038/s10038-020-00853-2. Epub 2020 Oct 10.
Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
桥小脑发育不良（PCH）目前分为 13 个亚组，通过下一代测序已经确定了许多与 PCH 相关的基因变异。PCH 型 1 是一种罕见的异质性神经退行性疾病。临床表现包括早发性严重发育迟缓、进行性运动神经元病以及小脑和脑桥萎缩。最近，在 4 名 PCH 型 1D（PCH1D）（MIM：618065）患者中发现了 EXOSC9 基因（MIM：606180）中的两个变体 NM_001034194.1：c.41T>C（p.Leu14Pro）和 c.481C>T（p.Arg161*）。EXOSC9 编码外体复合物的一个组成部分，对于 RNA 的正确加工和降解至关重要。我们在此报告了两个 PCH1D 家系的 EXOSC9 基因的双等位基因突变：c.239T>G（p.Leu80Arg）和 c.484dupA（p.Arg162Lysfs*3）在一个家系中，c.151G>C（p.Gly51Arg）在另一个家系中。虽然研究中的患者表现出与先前描述的 PCH1D 相似的临床特征，但发现其具有相对较大的智力发育（尽管仍然受到严重限制）和正常的脑桥结构。我们的发现扩展了双等位基因 EXOSC9 变异的临床后果。
