Background Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. Methods We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters. Results A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK , which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR , TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3 . When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3 . Conclusion CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54 -associated disorders. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as online supplementary information.

中文翻译：

---

细化突变谱和基因表型与脑桥小脑发育不全相关：多中心研究的结果

背景 脑桥小脑发育不全 (PCH) 包括一组遗传异质性疾病，其特征是脑桥和小脑同时发育不全以及不同的临床和影像学特征。目前的分类包括 13 个亚型，约 20 个已知致病基因。已经尝试描绘与特定 PCH 基因相关的表型谱，但临床和神经放射学特征在研究中并不一致，因此难以定义基因特异性结果。方法 我们对 56 名神经放射学诊断为 PCH 的先证者进行了深度临床和影像表型分析，他们接受了基于 NGS 的 PCH 基因面板测序和 MLPA 进行 CASK 重排。下一个，我们进行了基于表型的无监督层次聚类分析，以研究基因与特定表型簇之间的关联。结果 43 名先证者（77%）获得了基因诊断。最常见的致病基因是 CASK ，占近一半（45％），并且在女性中发生突变，偶尔在男性中发生突变。TSEN54 中的欧洲创始人突变 p.Ala307Ser 和 EXOSC3 中的致病变异分别占病例的 18% 和 9%。VLDLR 、 TOE1 和 RARS2 在单个患者中发生突变。我们只能确认少数先前报道的关联，包括与 TSEN54 的抖动和阵挛以及与 EXOSC3 的下运动神经元体征。当同时考虑多个特征时，只有 EXOSC3 才出现与表型簇的明确关联。结论 CASK是意大利PCH的主要致病基因。与 PCH 最常见的遗传原因相关的表型变异性比以前认为的要广泛，CASK 和 TSEN54 相关疾病之间存在显着重叠。所有与研究相关的数据都包含在文章中或作为补充信息上传。所有与研究相关的数据都包含在文章中或作为在线补充信息上传。