Clinical and Genetic Analysis of SMARCC2-Related Diseases in Three Chinese Patients

Coffin-Siris syndrome (CSS) is a rare, clinically and genetically heterogeneous disorder characterized by coarse facial features, microcephaly, intellectual disability (ID), developmental delay (DD), and hypo/aplastic digital nails and phalanges, typically of the 5th digit. CSS is an autosomal dominant disease resulting from mutations in genes encoding components of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. More than 300 CSS patients have been reported with variants in genes in the BAF pathway. Recently, patients carrying SMARCC2 variants have been reported to be associated with CSS8. However, as the number of cases increases, many patients do not exhibit the representative clinical symptoms of CSS. Additional case reports and clinical studies will contribute to a redefinition of SMARCC2-related disorders.

In this research, three patients with SMARCC2-related disorders from China were recruited. Genomic DNA was extracted from the peripheral blood leukocytes of these patients' parents and other family members, and then subjected to whole-exome sequencing as well as Sanger sequencing.

In the present study, two de novo variants (c.1311-3C>G, c.347G>A (p.Arg116His)) and a novel de novo variant (c.346C>T (p.Arg116Cys)) in the SMARCC2 gene were detected in three patients with neurodevelopmental disorders by whole exome sequencing. The clinical presentation of our patients supports a redefinition of SMARCC2-related diseases, which include mild to moderate DD, mild ID, facial dysmorphism, mild speech delay, hypotonia, feeding difficulties, brain abnormalities, attention deficit hyperactivity disorder (ADHD), and autistic behaviors. Furthermore, both the type of variant and its specific location may be contributing factors influencing the clinical outcomes.

Our study expands the genetic spectrum of SMARCC2 variants and detailed genotypic and phenotypic descriptions are important for the diagnosis of SMARCC2-related disease and accurate clinical management.