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

Abstract

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 a family of two adult CSS3 patients with a novel missense SMARCB1 mutation (c.1091A>C, p.Lys364Thr) identified through whole-exome sequencing (WES). Both patients exhibit selective difficulties in verbal learning and experience language delays. Additionally, the development of meningioma is confirmed in one of the patients. Mechanistic studies suggest that this missense mutation may abnormally activate the MAPK signaling pathway, which is implicated in the pathogenesis of tumor progression and neurodevelopmental disorders. This is the first reported case of a germline mutation in the SMARCB1 gene associated with both CSS3 and meningioma, thereby expanding the phenotypic spectrum of SMARCB1-related disorders.

1. Introduction

The mammalian SWI/SNF (Switch/sucrose non-fermentable) complex is an evolutionarily conserved, ATP-dependent chromatin remodeling complex that functions as an epigenetic modulator in the regulation of gene accessibility and expression [1–3]. Germline variants in genes encoding the core subunits of the SWI/SNF complex, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A, and ARID1B, have been implicated in neurodevelopmental disorders [4–8]. One such disorder is Coffin-Siris syndrome (CSS), a rare intellectual disability syndrome characterized by developmental delay, hypotonia, coarse facial features, feeding difficulties in infancy, and fifth digit anomalies [7,9–12]. Notably, mutations in SMARCB1 (also known as SNF5, BAF47, and INI1) are often associated with individuals exhibiting more severe intellectual disability and choroid plexus hyperplasia, a condition referred to as CSS3 (OMIM# 614608) [4,13,14].

In addition, genome-sequencing studies have revealed the extensive role of the SWI/SNF complex in cancer, with approximately 25% of all human tumors displaying aberrations in these genes [15–17]. SMARCB1 is recognized as a tumor suppressor, and its mutations have been linked to malignant rhabdoid tumors, schwannomas, and meningiomas, either individually or concurrently [18,19]. SMARCB1 consists of 385 amino acids, which include the N-terminal winged-helix DNA binding domain [20], two tandem repeat domains, and the highly conserved putative coiled-coil C-terminal domain (CTD) [14]. Notably, single-residue mutations closely associated with CSS and cancer are enriched in the CTD [14,21]. However, it remains unclear whether individuals with CSS3 concurrently develop tumors due to the limited understanding of the adult phenotypes of these patients. In this study, we identified a novel germline missense mutation in two members of a family with CSS3, one of whom developed meningioma. This report expands the phenotypic spectrum associated with SMARCB1-related disorders.