A novel mutation in SMARCB1 associated with adult Coffin-Siris syndrome and meningioma

SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex, which plays a crucial role in the regulation of gene expression. Germline mutations in the SMARCB1 gene have been linked to early childhood Coffin-Siris syndrome type 3 (CSS3), a rare congenital malformation syndrome characterized by severe developmental delay and intellectual disability. In this study, we report two adult CSS3 patients with novel missense SMARCB1 mutation (c.1091A>C, p.Lys364Thr) identified through whole exome sequencing (WES). Both two patients exhibited selective difficulties in verbal learning and language delay. Additionally, the development of meningioma was confirmed in one of the patients. Mechanistic studies indicate that this missense mutation may abnormally activates the expression of MAPK14, a gene implicated in the pathogenesis of tumor progression and neurodevelopmental disorders. This is the first reported case of a germline mutation in SMARCB1 gene associated with both CSS3 and meningioma, thereby expanding the phenotypic spectrum of SMARCB1-related neurodevelopmental disorders. Overall design: To investigate the impact of the missense mutation (c.1091A>C, p.Lys364Thr) on the function of the SMARCB1 protein, we established wild-type and mutant SMARCB1 overexpression IOMM-Lee cell lines via lentiviral transfection. Subsequently, we examined the effects of this mutation through transcriptome analysis, focusing on their influence on gene expression profiles.