A multi-omics approach to characterize a deep intronic ARID1A deletion in Coffin-Siris syndrome

Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARID1A variants are responsible for 6-8% of CSS cases. We report a female individual with clinical and phenotypic manifestations suggestive of CSS. Trio exome sequencing failed to identify a causative variant. Short-read genome sequencing revealed a de novo 24 kb intronic deletion in ARID1A. Methylation analysis showed a BAFopathy-like profile supporting pathogenicity. Transcriptome analysis and RT-PCR detected a rare aberrant splicing event in a subset of ARID1A transcripts: the activation of a pseudoexon, resulting in a premature termination codon as the underlying pathomechanism. This is the first non-coding pathogenic alteration reported in ARID1A and the second in a CSS gene. This case highlights how the combination of genomic, transcriptomic and epigenomic data is crucial to improve diagnostic accuracy in unsolved cases.