A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

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.

Automated summary

Our study aimed to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA). Whole-exome sequencing identified rare single heterozygous variants in ATP7B, SORL1, SETX, and FOXP1 genes. Functional analysis revealed changes in splicing pattern and lower mRNA levels in the patient's fibroblasts, indicating loss-of-function as the underlying mechanism. The study also highlighted the association of CBS-PNFA phenotype with the ATP7B pathogenic variant p.H1069Q, previously linked to Wilson's disease and early onset Parkinson's disease. Furthermore, it expanded the clinical spectrum related to well-known disease genes and suggested the hypothesis of oligogenic inheritance. The study emphasized the possible relevance of the FOXP1 gene to adult-onset progressive apraxia of speech, which requires further investigation.