-
Discovery via Whole-Exome Sequencing (WES): The study highlights the pivotal role of whole-exome sequencing in identifying the molecular etiology of Coffin–Siris syndrome (CSS), confirming that the majority of sporadic cases arise from de novo autosomal dominant mutations.
-
The BAF Complex Connection: CSS is primarily a disorder of chromatin remodeling caused by pathogenic mutations across multiple subunit genes encoding the BAF (mSWI/SNF) complex.
-
Core Mutated Genes Identified: Screening patient cohorts led to the identification of causative mutations across five main BAF complex genes:
-
ARID1B and ARID1A
-
SMARCB1 and SMARCA4
-
SMARCE1
-
-
Differential Diagnosis & Phenotypic Overlap:
-
Nicolaides–Baraitser Syndrome (NCBRS): A patient initially diagnosed with CSS carrying a SMARCA2 mutation was reevaluated and reclassified as having NCBRS, demonstrating clinical overlap between BAF-related disorders.
-
Börjeson–Forssman–Lehmann Syndrome (BFLS): Abnormalities in PHF6 were also noted in a subset of patients presenting with CSS-like features, highlighting another important differential diagnosis.
-
-
Genetic Heterogeneity: Across combined screening cohorts, a high percentage of patients (~52% or 37 out of 71) had identified mutations in one of the five core BAF genes, leaving room for additional novel gene discoveries within the spectrum.
