PDF(Pubmed)
Abstract：
Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann-Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann-Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.
摘要：
POLR3A内的双等位基因致病变异与一系列遗传性疾病有关。其中,较不常见的情况是Wiedemann-Rautenstrauch综合征（WRS），也被称为新生儿孕激素综合征。这种综合征通常表现在新生儿，以生长迟缓为特征，明显的全身性脂肪营养不良，具有明显的局部脂肪积累，稀疏的头皮头发，和不典型的面部特征。我们的目的是阐明Wiedemann-Rautenstrauch综合征（WRS）的潜在分子机制。在这项研究中,我们介绍了一例诊断为WRS的7岁女性患者的临床病例.利用全外显子组测序（WES），我们确定了一个新的错义变体c.3677T>C（p。Leu1226Pro）在POLR3A基因（NM_007055.4）中与两个顺式内含子变体c.190922G>A和c.3337-11T>C.通过分析来自成纤维细胞的mRNA，我们再次证实了c.3337-11T>C变体的影响剪接的性质。此外，我们的调查导致了c.3677T>C的重新分类(第Leu1226Pro）变体作为可能的致病性变体。因此,这是第一例证明来自俄罗斯联邦的Wiedemann-Rautenstrauch综合征患者的分子遗传学。到目前为止，已经记录了有限数量的临床病例；因此，拓宽POLR3A基因表型和分子变化之间的联系将大大有助于全面了解POLR3A相关疾病的分子基础。
