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High Diagnostic Yield (71%): Screening a cohort of 63 patients clinically diagnosed with Coffin–Siris syndrome (CSS) identified causative variants in 45 individuals (71%) across six core BAF complex genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1).
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ARID1B Dominated the Cohort: Mutations in ARID1B accounted for 68% of all identified variants, confirming it as by far the most frequent genetic cause of CSS.
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Somatic Mosaicism in ARID1A: All four pathogenic variants identified in ARID1A were found to be mosaic (present in only a subset of cells), explaining some of the phenotypic variability and potential severity differences associated with this gene.
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Genotype–Phenotype Correlations:
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SMARCB1 Variants: Associated with the most marked/severe physical features, as well as the most severe cognitive impairment and growth restriction, but the least pronounced distal limb (finger/toe) abnormalities.
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ARID1A Variants: Produced the most marked distal limb anomalies (such as hypoplastic/absent fingernails and terminal phalanges).
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ARID1A & ARID1B: Showed the greatest clinical variability, ranging from mild/nonsyndromic intellectual disability to full classic CSS.
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Variant Classification & Parental Testing: Using public databases (Exome Variant Server), variants in ARID1A, ARID1B, and SMARCB1 could be reliably classified as pathogenic vs. benign. However, for SMARCA4, SMARCA2, and SMARCE1, missense variants were harder to interpret without parental testing to confirm de novo status.
