背景:小脑发育不全是一个总称,描述了一组异质性的产前神经退行性疾病,主要影响脑桥和小脑,与25个基因相关的17种类型。然而,某些类型的PCH缺乏足够的信息,这突出了调查和引入更多病例以进一步阐明临床的重要性,放射学,和这些疾病的生化特征。这项研究的目的是提供对PCH的深入审查,并确定12个临床证实的PCH的伊朗不同家庭的疾病基因及其遗传模式。
方法:本研究中的病例是根据综合遗传服务中心提供的表型和遗传信息进行选择的。全外显子组测序(WES)用于发现参与者的潜在遗传病因问题,和Sanger测序用于确认任何可疑的改变。我们还进行了全面的分子文献综述,以概述PCH各种亚型的遗传特征。
结果:这项研究根据所涉及的基因将PCH的潜在病因分为三类。还包括12名患者,其中11人来自近亲。在8个基因中发现了10种不同的变异,所有这些都与不同类型的PCH有关。报告了六种新颖的变化,包括SEPSECS,TSEN2、TSEN54、AMPD2、TOE1和CLP1。几乎所有患者都出现发育迟缓,低张力,癫痫发作,小头畸形是常见特征。在7型和9型PCH中,MR波谱中斜视和乳酸水平升高首次成为新的表型。
结论:本研究将先前记录的表型和基因型与独特的新表型和基因型合并。由于PCH的多样性,我们为检测和诊断这些异质性疾病提供了指导.此外,由于某些关键条件,比如脊髓性肌萎缩症,可以是鉴别诊断,提供具有新的变异和临床发现的病例可以进一步扩大这些疾病的遗传和临床范围,并有助于更好的诊断。因此,首次报道了6种新的遗传变异和新的临床和临床发现。需要进一步的研究来阐明PCH的潜在机制和潜在治疗靶点。
BACKGROUND: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth
review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH.
METHODS: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants\' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature
review to outline the genetic features of the various subtypes of PCH.
RESULTS: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9.
CONCLUSIONS: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.