Case Report: novel mutations in SMARCA4 cause Coffin-Siris syndrome type 4 with autism spectrum disorder without visual impairment in one patient.
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Coffin-Siris syndrome type 4 (CSS4; OMIM 614609) is a rare autosomal dominant disorder caused by variants in SMARCA4, encoding the BRG1 ATPase subunit of the BAF chromatin-remodeling complex. Although classically characterized by intellectual disability, distinctive facial features, and fifth digit hypoplasia, the phenotypic spectrum is broad and includes autism spectrum disorder (ASD) without typical somatic features. We report a 3-year-old Chinese girl with global developmental delay, ASD features, characteristic facial features, and a documented normal ophthalmologic examination in whom whole-exome sequencing identified a novel heterozygous de novo frameshift duplication, c.4767dup (p.Ser1590Ilefs*39), in SMARCA4 (NM_003072), classified as Pathogenic (PVS1+PM2_Supporting + PM6). Notably, she lacked fifth digit hypoplasia and had no structural ocular anomalies on detailed ophthalmologic evaluation. A systematic review of the literature identified 39 genetically confirmed SMARCA4-related CSS4 cases; combined with our patient, 40 cases were analyzed. Intellectual disability was universal (100%), ASD manifestations occurred in 42.5%, and fifth digit hypoplasia was present in only 55.0%. Truncating variants (37.5% of the cohort) showed descriptive trends toward higher prevalence of fifth digit hypoplasia and ocular abnormalities than missense variants, though these differences did not reach statistical significance. Our proband, despite carrying a truncating variant, presented without classic digital anomalies or ocular involvement, underscoring that even loss-of-function alleles can produce atypical CSS4 phenotypes. For children with developmental delay, ASD, and distinctive facial features-regardless of the presence of classic digital anomalies-genetic testing for SWI/SNF complex genes should be considered. Given current limited evidence, carriers of truncating variants should be counseled regarding potential tumor predisposition, and individualized surveillance strategies may be considered pending further data.