我们的目的是分析被诊断为进行性非流畅性失语(CBS-PNFA)的早发性皮质基底综合征患者的表型遗传相关性。以言语占优势性失用症为特征,伴有突出的右侧上肢肢体动力学失用症,异形肢体现象,Synkinesis,肌阵鸣,轻度皮质感觉丧失,和右侧半球形忽视。全外显子组测序(WES)在ATP7B中鉴定出罕见的单个杂合变体(c.3207C>A),SORL1(c.352G>A),SETX(c.2385_2387delAAA),和FOXP1(c.1762G>A)基因。功能分析显示,SETX基因的缺失改变了剪接模式,在患者的成纤维细胞中伴随着较低的SETXmRNA水平,提示功能丧失是潜在的机制。此外,患者的成纤维细胞表现出线粒体结构改变,连通性降低,与对照个体相比。这是CBS-PNFA表型与最常见的ATP7B致病变体p.H1069Q的首次关联,以前与威尔逊病有关,和早发性帕金森病。这项研究扩展了与众所周知的疾病基因变异相关的复杂临床谱,例如ATP7B,SORL1,SETX,和FOXP1,证实了寡遗传的假设。迄今为止,FOXP1基因与神经发育性言语障碍有关,虽然我们的研究强调了它可能与成人发作的进行性言语失用症有关,这保证了进一步的研究。
Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient\'s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient\'s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson\'s disease, and early onset Parkinson\'s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study.